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Cardiovascular Adaptations to Exercise Training

Ylva Hellsten*1 and Michael Nyberg1

ABSTRACT
Aerobic exercise training leads to cardiovascular changes that markedly increase aerobic power
and lead to improved endurance performance. The functionally most important adaptation is the
improvement in maximal cardiac output which is the result of an enlargement in cardiac dimen-
sion, improved contractility, and an increase in blood volume, allowing for greater filling of the
ventricles and a consequent larger stroke volume. In parallel with the greater maximal cardiac
output, the perfusion capacity of the muscle is increased, permitting for greater oxygen delivery.
To accommodate the higher aerobic demands and perfusion levels, arteries, arterioles, and cap-
illaries adapt in structure and number. The diameters of the larger conduit and resistance arteries
are increased minimizing resistance to flow as the cardiac output is distributed in the body and the
wall thickness of the conduit and resistance arteries is reduced, a factor contributing to increased
arterial compliance. Endurance training may also induce alterations in the vasodilator capacity,
although such adaptations are more pronounced in individuals with reduced vascular function.
The microvascular net increases in size within the muscle allowing for an improved capacity for
oxygen extraction by the muscle through a greater area for diffusion, a shorter diffusion distance,
and a longer mean transit time for the erythrocyte to pass through the smallest blood vessels.
The present article addresses the effect of endurance training on systemic and peripheral cardio-
vascular adaptations with a focus on humans, but also covers animal data. © 2016 American
Physiological Society. Compr Physiol 6:1-32, 2016.

Introduction in the muscle is increased many-fold. Shear stress is sensed by

It has long been known that endurance training leads to adap-
tations in the cardiovascular system (61). Human studies in
the 1960s and onward demonstrated that endurance train-
ing results in increases in cardiac output, increased vascular
conductance, a greater perfusion capacity of the muscle, and
a greater oxygen extraction, with a consequent increase in
aerobic power (378, 380). At this time, the muscle biopsy
technique was also beginning to be used in humans allow-
ing for determinations of peripheral adaptations in the trained
skeletal muscle and revealing an increased oxidative capacity
and increased capillary density in trained muscle (8, 29). In
the 1980s, Bengt Saltin and colleagues developed the single-
leg knee extensor model and used it in combination with
the thermodilution technique to assess skeletal muscle blood
flow (7, 9) and provide further evidence for the theory of
a central limitation in oxygen transport capacity (62, 76).
Since this time period and partly with the use of these meth-
ods, a large number of studies have addressed the effects of
endurance training on adaptations in the cardiovascular sys-
tem and the underlying mechanisms. Such studies have pro-
vided insight specifically into the dimensional and functional
improvements in the heart and how vascular function and the
macro and microvascular growth is affected by endurance
training. In terms of mechanisms, it has clearly been shown
that shear stress is a central factor in vascular adaptations
to training. Shear stress, which is the force that the blood
applies to the endothelial cells as it flows through the blood
vessel, is enhanced during endurance training when perfusion
mechanosensors on the endothelial cells leading to an acute
increase in vascular conductance but, more importantly, it also
influences the expression of proteins in the vascular wall of
significance for vascular function and vascular growth. Both
changes in arterial dimensions, and growth of arterioles and
capillaries are believed to be highly influenced by shear stress.
The present article discusses evidence for adaptations in
the cardiovascular system in response to endurance training
and takes the reader through adaptations and related mech-
anisms in cardiac muscle, blood, arterial structure, and the
microvasculature in skeletal muscle but also briefly touches
upon adaptations in tissues other than the active muscle. The
review has a focus on humans but also includes data from
animal studies.
Central Adaptations to Exercise Training
Cardiac adaptations to exercise training
At the onset of exercise, heart rate and stroke volume increase
so that cardiac output closely matches the metabolic demand
of the working skeletal muscles (182, 289). Cardiac output,
* Correspondence to yhellsten@nexs.ku.dk
1 Department of Nutrition, Exercise and Sports, University of
Copenhagen, Copenhagen, Denmark
Published online, January 2016 (comprehensivephysiology.com)
DOI: 10.1002/cphy.c140080
Copyright © American Physiological Society.

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Cardiovascular Effects of Endurance Training
the product of heart rate (beats min−1 ) and stroke volume
(mL min−1 ), may increase from ∼5 L min−1 at rest to ∼15
L min−1 in young females (449) and ∼20 L min−1 in young
males (288, 378) and up to ∼25 to 30 (449) and ∼35 to 40 L
min−1 (103) in elite female and male athletes, respectively,
during maximal exercise engaging a large muscle mass. This
pronounced effect of exercise training on maximal cardiac
output would be expected to entail a structurally and func-
tionally improved heart in the trained state. This cardiac train-
ing adaptation was first described more than 100 years ago
by Henschen (179), using only a basic physical examina-
tion with careful percussion to identify enlargement of the
heart due to athletic activity in cross-country skiers. Hen-
schen concluded that dilatation and hypertrophy of the left
and right side of the heart were present in trained individuals
(179). The use of chest radiography in the 1950s and 1960s
(350, 367) and development and technological refinement of
echocardiography throughout the 1970s and 1980s have pro-
vided the methodology for a detailed evaluation of training-
induced morphologic and functional changes in the trained
heart. Accordingly, increased end-diastolic dimensions of the
right (RV) and left ventricle (LV), LV hypertrophy, increased
LV mass, and increased volume of the left atrium (LA) are
now well-established hallmarks of what has been defined as
the athlete’s heart. With regard to the dimensions of the heart,
it should be noted that body size has a large influence on
heart size and when comparing absolute dimensions between
subjects one should take this variable into account. For this
reason, women in general have smaller cardiac dimensions
compared to men (332).
The increase in heart rate is responsible for the major-
ity of cardiac output augmentation during exercise. How-
ever, maximal heart rate is relatively unaltered with exer-
cise training, with some evidence indicating that heart rate
may be reduced during maximal exercise with training (463).
Consequently, the large increase in cardiac output associ-
ated with exercise training is the result of a larger stroke
volume. Stroke volume rises during exercise as a result of
increases in LV end-diastolic volume and, to a lesser extent,
sympathetically mediated reduction in end-systolic volume.
LV end-diastolic volume is determined by diastolic filling,
which is determined by a complex interplay between heart
rate, intrinsic myocardial relaxation, ventricular compliance,
ventricular filling pressures, atrial contraction and pericardial
and pulmonary constraints (18). An increase in stroke volume
with exercise training could, therefore, potentially be a result
of changes in one or more of these variables.
The left ventricle
The majority of data characterizing left ventricular structure
and function in trained individuals comes from cross-sectional
studies. Although this approach does not allow for definite
conclusions regarding the temporal nature and dose-response
relationship between exercise and cardiac remodeling, find-
ings from these studies have provided valuable insight on
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Comprehensive Physiology
characteristics of the LV in trained subjects. Accordingly,
increased LV end-diastolic diameter (331, 333, 361), LV wall
thickness (333, 361) and LV mass (333, 338) have consis-
tently been reported in endurance athletes. The most extreme
cavity dimension and/or wall thickness have been reported
in elite male rowers, cross-country skiers, cyclists and swim-
mers with large body sizes (331,333,410). The findings on LV
end-diastolic diameter have been confirmed in longitudinal
training studies in which rowing for 7 months (453) and pro-
fessional cycling for 3 years (2) were associated with increases
in cavity dimension of LV (from 51.5 to 53.3 mm and from
58.3 to 60.3 mm, respectively). Furthermore, one year of
progressive endurance exercise training performed by previ-
ously sedentary male and female subjects lead to increases
in LV mass and LV end-diastolic volume (13). Interestingly,
the LV responded to the initiation of training (0-6 months,
lower intensity training) with an increase in LV mass without
a change in LV end-diastolic volume whereas additional three
months of training (high-intensity interval) lead to an increase
in LV end-diastolic volume which restored the baseline mass-
to-volume ratio (13).
The hemodynamic changes that occur during exercise
constitute the primary stimulus for cardiac remodeling.
Accordingly, exercise can be separated (although consider-
able overlap exists) into two principal forms of physical
activity: (i) endurance exercise characterized by sustained
elevations in cardiac output with reduced peripheral vascular
resistance (i.e., long-distance running, cycling, rowing, and
swimming) and (ii) strength training characterized by short
but intense bouts of increased peripheral vascular resistance
and only slightly elevated cardiac output (i.e., weightlifting,
track-and-field throwing events). The notion that these over-
all differences in cardiac loading with either endurance or
strength training lead to different exercise-induced adapta-
tions in cardiac structure was first introduced in 1975 (286).
In this study (286), athletes exposed to endurance train-
ing demonstrated eccentric LV enlargement (increased LV
end-diastolic volume and mass) whereas athletes exposed
to strength training demonstrated concentric LV hypertro-
phy, characterized by normal LV end-diastolic volumes, but
increased wall thickness and mass. Recent systematic reviews
and meta-analysis suggest that the magnitude of eccentric LV
hypertrophy that results from endurance exercise training is
typically more pronounced than the concentric hypertrophy
that accompanies strength training (18, 443).
Changes in LV function have been extensively evaluated
in trained individuals. Endurance training leads to enhanced
early diastolic LV filling (19,307,337) and a more rapid filling
of the heart during high-intensity exercise (109). This rapid
filling is the result of mechanical restorative forces due to
the remodeling of the heart, which markedly augment the
transmittal intraventricular pressure gradient whereby blood
is rapidly sucked from the LA into the apex of LV (462).
This diastolic suction and hence rapid filling of LV is likely to
explain the observation that there is a continuous rise in stroke
volume in highly trained endurance individuals (132, 467) as
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Comprehensive Physiology Cardiovascular Effects of Endurance Training

opposed to less active and sedentary subjects who display a (A) 200
plateau around 40% to 50% of VO2max (15,132). In addition to
diastolic suction, cardiac chamber compliance has also been
shown to be enhanced in athletes, resulting in a large end-
diastolic LV volume and a greater use of the Frank-Starling

Heart rate (bpm)

mechanism (257). Notably, one year of progressive exercise 150
training was only associated with a modest increase in LV
distensibility and compliance and these posttraining values
were substantially below that observed in elite athletes (13). In
contrast to diastolic function, systolic function as assessed by Elite
100 Trained
LV ejection fraction, is generally normal among athletes (18) Untrained
and the rate of ventricular emptying plays only a modest role
in the augmentation of stroke volume during exercise (132). 0
Collectively, the adaptations in LV diastolic function are the (B) 0 2 4 6 8
225
primary mechanisms underlying the larger LV end-diastolic
volume and hence larger stroke volume in trained subjects.
200
Myocardial blood flow per gram of tissue is lower in

Stroke volume (mL)

highly trained endurance athletes both at rest (171, 172) and
during exercise performed at the same absolute workload 175
(171,239) and athletes have higher myocardial oxygen extrac-
tion facilitated by longer blood mean transit time (171). Evi- 150
dence from animal studies suggests that a larger capillary sur-
face area and a more efficient blood flow distribution through 125
the myocardium contribute to the increased oxygen extrac-
tion in the trained heart (245). Moreover, myocardial O2 per 100
gram of tissue at rest and during exercise at the same abso- 0
lute workload is lower in athletes (171). Collectively, these 0 2 4 6 8
(C) 40
findings suggest that the improved cardiac pump function with
training is related to a larger circulatory and metabolic reserve.
Cardiac output (L min–1)

30
The right ventricle
Endurance exercise of moderate to high intensity requires 20
that both the LV and RV receive and eject large quantities
of blood and without any significant shunting both cham-
bers will inevitably have to enhance structure and function 10
to a somewhat similar extent. In accordance with this con-
cept of balanced, biventricular enlargement, RV enlargement
has been shown to parallel LV enlargement (387, 388). The 0
impact of strength training on the RV remains uncertain due 0 2 4 6 8
to inconsistent and limited data (18). Systemic VO2 (L min–1)

The left atrium
Several small cohort studies were the first to report LA
enlargement in trained athletes (167, 189). This structural
adaptation is in line with later observations (81, 195) and
cumulative lifetime exercise training hours have been shown
to be an important determinant of LA size (454).
Cardiac output: From rest to maximal exercise
One of the hallmarks of cardiovascular training is a lower-
ing of heart rate at rest (sinus bradycardia) and during exer-
cise at any absolute level of submaximal oxygen uptake (35)
(Fig. 1). Systemic oxygen demand and hence cardiac output
Figure 1 Heart rate (A), stroke volume (B), and cardiac output (C)
in relation to systemic V̇ O2 in untrained and trained subjects and elite
athletes.
at rest is largely unaffected by exercise training (26,415), and
the bradycardia is, therefore, likely secondary to the training-
induced increase in stroke volume. The autonomic mecha-
nisms underlying the decrease in heart rate at rest is a result
of an increase in vagal tone and a decline in the intrinsic heart
rate, while a reduction in sympathetic activity has minimal
impact (366, 405).
The increase in heart rate following exercise onset is medi-
ated by a combination of vagal withdrawal and β-adrenergic
stimulation (123, 359) and an essentially linear relationship

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Cardiovascular Effects of Endurance Training
35
MSNA
Venous norepinephrine
30
MSNA (burst min–1)
25
20
15
10
5 0.5
0 0.0
Untrained Trained
Figure 2 Skeletal muscle sympathetic nervous activity (MSNA) during
knee-extensor exercise and venous norepinephrine concentrations dur-
ing cycling exercise in the untrained and trained state. MSNA was mea-
sured by microneurography in the resting leg. Adapted from (346) and
(457) with permission of the American Physiological Society. MSNA =
Muscle sympathetic nerve activity.
exists between relative workload and heart rate during exer-
cise that is independent of training status (35, 122). Simi-
lar to resting conditions, cardiac output at a given absolute
submaximal workload is not significantly different follow-
ing exercise training as oxygen demand is also unaltered
(26, 415). The unchanged cardiac output is the result of a
larger stroke volume and lower heart rate (132, 415). The
mechanisms underlying the lower heart rate during submax-
imal exercise are still unclear but are likely to be related to
both autonomic and nonautonomic factors. Exercise training
results in diminished sympathetic drive for a given level of
exercise (75, 346, 405, 457) (Fig. 2) whereas training does not
appear to induce a decrease in vagal tone during exercise. In
addition, some evidence has been provided for that increases
in heart volume lowers intrinsic heart rate (224, 258). The
increase in stroke volume during exercise at a given abso-
lute workload in the trained state is a result of an increase
in blood volume, an augmented left ventricular end-diastolic
volume, and cardiac preload (198,236) as well as a lower car-
diac afterload (arterial pressure) (132,296). Notably, evidence
suggests that cardiac output during exercise is regulated by
peripheral oxygen demand (16, 156) and that this regulation
is independent of training status (296).
To what extent heart rate during maximal exercise is
altered with exercise training remains a topic of debate. Never-
theless, maximal heart rate has been reported to be decreased
by 3% to 7% with training in a large number of studies (463).
At least some of the mechanisms underlying a decrease in
maximal heart rate are likely to be similar to those underlying
resting and submaximal bradycardia. One such mechanism
could be a receptor downregulation as β-adrenergic blockade
has been shown to abolish the difference in maximal heart
rate between sedentary and trained subjects due to a less sig-
nificant reduction in heart rate in the trained subjects (215).
From a functional perspective, a lower maximal heart rate will
allow for increased filling time, which is likely to be important
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Comprehensive Physiology
3.0 for preservation of a large end-diastolic volume and stroke
volume (103, 132), of which the latter may exceed that of
Venous norepinephrine (ng mL–1)
2.5 sedentary subjects by ∼60% to 70% during maximal exercise
(54, 103, 467). Such an advantageous functional consequence
2.0
of an increased filling time is in line with that restrictions in
filling time appear to compromise ventricular filling, stroke
1.5
volume, and cardiac output during maximal exercise in trained
1.0 individuals (303).
The capacity to produce a very high power output for
a prolonged period of time is essential for endurance per-
formance. To support the very high rates of oxygen uptake
required, the heart must generate a high cardiac output that
is achieved by a large stroke volume. This training-induced
increase in stroke volume is in turn mediated predominantly
by a large LV end-diastolic volume.
Blood Volume Response to
Exercise Training
During exercise, plasma volume is acutely reduced in propor-
tion to metabolic and/or thermal demands and the resulting
loss in plasma volume is accompanied by increased electrolyte
concentrations and osmolality that leads to activation of the
renin-angiotensin-aldosterone cascade and ultimately renal
water retention (71). Exercise training leads to an expansion
of blood volume (hypervolemia) via an aldosterone-sodium
retention mechanism along with increases in plasma albumin
content (70). Cross-sectional data have shown that exercise
training is associated with a 20% to 25% larger blood vol-
ume in trained individuals and ∼50% larger blood volume
in elite athletes compared to untrained individuals (69, 170)
(Fig. 3). The fast rate at which exercise-induced hypervolemia
occurs is demonstrated by the fact that one single exercise
bout can increase blood volume by 10% to 12% within 24
h (130, 341). The hypervolemia appears to reach a plateau
at around 10 to 14 days of training and virtually all of this
increase in blood volume is due to increased plasma vol-
ume as erythrocyte mass does not change significantly within
this timeframe (69). As training continues, erythrocyte vol-
ume expansion is observed and increases (with most of the
effect observed within 30 days) until plasma and erythrocyte
volume is 8% to 10% above the pretraining level (69). The
result is a hematocrit that returns to an only slighter lower
level than before training initiation (385). A modestly lower
hematocrit with training is in congruence with cross-sectional
data demonstrating that athletes have ∼1% lower hematocrit
than sedentary controls (170). Whereas the control of erythro-
poiesis in hypoxia and anemic hypoxia is well understood, the
signals stimulating erythropoiesis upon training in normoxia
are unclear, but may involve an exercise-induced increase in
androgens that stimulate erythropoietin (EPO) release and
an increase in catecholamines and cortisol that stimulate the
release of reticulocytes (immature erythrocytes) from bone
marrow and possibly EPO release (271).
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Comprehensive Physiology Cardiovascular Effects of Endurance Training

(A) 10 and stroke volume. Reestablishing blood volume to a level

similar to that observed before a 6-week training interven-
tion by phlebotomy, abolished the training-induced change in
8
maximal cardiac output, suggesting that the training-induced
Blood volume (L)

change in maximal cardiac output following a short period of

6 exercise training is a consequence of an increase in blood vol-
ume (39). Furthermore, a large part of the difference in stroke
4 volume between trained and untrained has also been sug-
gested to be related to differences in blood volume (198,236).
2 Exercise training also activates de novo protein synthesis and
leads to a more dilute sweat. These adaptations will help to
0
compartmentalize fluid within the vascular space which will
(B) 5 5 help to keep blood volume normal via fluid shifts during peri-
ods of sweat loss, due to elevations in oncotic pressure and
Erythrocyte volume
Plasma volume
intravascular electrolyte levels (69).
4 4
Hemoglobin is an excellent buffer, and an increase in
Erythrocyte volume (L)

Plasma volume (L)

3 3
2 2
1 1
0 0
(C) 50
Hematocrit (%)
hemoglobin mass enhances the buffering capacity of the
blood (58). The training-induced increase in hemoglobin mass
could, therefore, potentially facilitate a higher lactate and pro-
ton release from active skeletal muscle due to a higher diffu-
sion gradient from the interstitium to the blood and improve
the capacity to produce energy via anaerobic pathways. How-
ever, experimental data for such an effect is lacking.
Indications of the performance enhancing effects of the
training-induced increase in erythrocyte mass, plasma and
blood volume can be seen from studies where blood has
been drawn and then reinfused after several weeks to increase
these variables (also known as blood doping). Accordingly, an
improvement in VO ̇ 2max and endurance performance (longer

45 exercise time at a given workload, greater mean power output

40
0
Untrained Trained Elite
Figure 3 Blood volume (A), erythrocyte and plasma volume (B), and
hematocrit (C) in untrained and trained subjects and elite athletes.
The hypervolemia associated with exercise training
reflects a larger total body water volume (68) which increases
interstitial fluid available to the sweat glands and allows for a
greater plasma volume to perfuse skin to enhance conductive
heat exchange. Accordingly, hypervolemia following exercise
training is related to increased sweat rate and evaporative cool-
ing during exercise (68, 70). In addition to thermoregulatory
advantages, hypervolemia and the associated lower hema-
tocrit and blood viscosity have been proposed to decrease
the workload of the heart (104) due to a greater filling of
the heart and lower peripheral resistance. Studies employing
acute expansion of blood volume by intravenous infusion of
dextran (198, 236) or albumin (115) have demonstrated that
increased blood volume significantly influences cardiac per-
formance by increasing cardiac preload, ventricular filling
or speed during a time trial) with this intervention has been a
general finding (47,102,439,455). Notably, blood doping also
increases hematocrit and hence the oxygen carrying capacity
of the blood, which is in contrast to the normal physiolog-
ical training response where hematocrit is slightly lowered
(170), and care should, therefore, be taken when extrapo-
lating findings from these studies. Nevertheless, data from
trained endurance athletes suggests that the increase in ery-
throcyte mass (208, 385) and plasma and blood volume (266)
are important training adaptations for endurance exercise
performance.
Effect of Exercise Training on
Blood Pressure at Rest and
During Acute Exercise
The long-term control of blood pressure has been recognized
as a complex mixture of neural, hormonal and intrinsic fac-
tors involving the brain, heart, vasculature, and especially the
kidneys due to its control of fluid balance. In a mathemati-
cal model composed of hundreds of equations, Guyton and
co-workers proposed that a volume increase in the vascular
system would lead to an increase in blood pressure (157).
Nevertheless, despite the effects of training on blood volume

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Cardiovascular Effects of Endurance Training
it is well established that endurance training reduces blood
pressure at rest in both normotensive and hypertensive sub-
jects, with a more pronounced effect in hypertensive sub-
jects (73). The mechanisms underlying this effect of exercise
training remain undisclosed, but are likely to be multifacto-
rial and include vascular remodeling (169) and/or changes
in peripheral vascular function (419), sympathetic nervous
activity (73, 244, 300), function of the nitric oxide (NO) and
prostanoid system (315), and the renin-angiotensin system
(73). With regard to the sympathetic nervous system, the role
of skeletal muscle sympathetic nervous activity (MSNA) for
the training-induced reduction in blood pressure is likely to be
limited as training does not reduce MSNA at rest (393). Inter-
estingly, in healthy older humans exercise training has even
been shown to be associated with elevated basal MSNA (310).
Exercise training leads to a reduction in blood pressure
and sympathetic drive during acute submaximal exercise per-
formed at the same absolute intensity when muscles of the
lower limb are recruited (75,110,296,346,457) (Fig. 2). Con-
versely, exercise training does not appear to affect the MSNA
response when forearm exercise is performed (393), suggest-
ing that the effects of exercise training on MSNA during
exercise may be related to the limb and/or the size of muscle
mass engaged in exercise. The effect of training on MSNA
could be related to alterations in both central command and
the pressor response originating from the contracting skeletal
muscle as both influence sympathetic nervous activity (282).
The pressor response is thought to be the result of affer-
ent input coming from group III and IV fibers that respond
to mechanical distortion and changes in the chemical envi-
ronment, respectively (225). A lower skeletal muscle lactate
production associated with exercise training could be one
important chemical influence as in animal models, blockade
of acid sensitive ion channels has been shown to attenuate
the pressor response (168) and a relationship between pH
and sympathetic nervous activity has been reported (445).
Furthermore, training also reduces central command output
as evidenced by attenuation of the blood pressure and heart
rate response to acute exercise in the contralateral untrained
limb (110). As previously described, heart rate is lower during
exercise engaging a trained muscle group. Despite this effect
on heart rate, stroke volume still remains higher in the trained
state which primarily is the result of the lower arterial blood
pressure and hence cardiac afterload (296).
Arterial Remodeling in Response to
Exercise Training
It is well established that changes in hemodynamic forces,
including shear stress and transmural pressure, can lead to
remodeling arteries and arterioles (1,45,268,302). In humans,
some of the clearest evidence for remodeling is observed in, on
one hand, individuals with hypertension who have increased
arterial wall thickness and reduced lumen diameter and, on
the other hand, endurance trained individuals who display a
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Comprehensive Physiology
reduced arterial wall thickness and an increased lumen diam-
eter (147, 302).
The function of conduit and resistance arteries is to allow
for transport of blood from the heart to the different organs
and the diameter and elastic properties of these arteries should
optimally be adequate so as not to limit the blood flowing from
the heart. In general, although the diameter of larger resis-
tance arteries may contribute to overall vascular resistance,
the greatest resistance is located further down in the smaller
arterioles within organs, thus structural changes at this level
may be more important.
In comparing muscle blood flow during intense exercise
with a smaller versus larger muscle mass, it is clear that per-
fusion of muscle during whole body exercise is limited by the
magnitude of the cardiac output (52,377,395,446). Therefore,
as cardiac output is increased with endurance training, the per-
fusion capacity of the muscle increases during intense exercise
with larger muscle groups (377), but maximal perfusion dur-
ing one-leg exercise, for which there is no central limitation,
is also increased (353). To accommodate the higher perfu-
sion rates, the arteries undergo structural adaptations leading
to an increased diameter and reduced wall thickness and the
volume of the arteriolar net is increased.
Effects of training on arterial diameter
Conduit arteries Conduit artery dimensions can be
assessed by ultrasound Doppler technique with good accuracy
in humans (426). Cross-sectional studies comparing differ-
ent groups of athletes including tennis players, road cyclists,
runners, and wheel-chair athletes with sedentary individu-
als, have demonstrated that the diameter of muscular conduit
arteries is larger in trained than untrained muscle (90,200,372,
389). This observation also holds true for intraindividual com-
parisons of the dominant and nondominant arm of tennis play-
ers (200), for the preferred arm of squash players (371) and
for trained below knee one-leg amputees (200). In accordance
with the findings from cross-sectional studies, longitudinal
studies provide evidence for that a period of aerobic training
of 6 to 12 weeks is sufficient to increase the diameter of the
femoral artery (90, 283). In further support of a relationship
between training and conduit artery dimensions is the obser-
vation that femoral arterial diameter and maximal oxygen
uptake correlate well (r = 0.91) in young healthy men (345).
Some studies on human coronary arteries (183, 234) have
shown that the resting diameter of endurance trained individu-
als is similar to that of sedentary individuals. However, Pelic-
cia and co-workers reported a relationship between coronary
artery diameter and cardiac dimension in top-level athletes,
indicating a training-induced enlargement of coronary arter-
ies, although it should be kept in mind that a genetic contribu-
tion cannot be excluded in such measurements (334). More-
over, at a functional level, the increase in coronary diameter
with either the NO donor nitroglycerin (166), adenosine infu-
sion (183), or dipyridamole, an inhibitor of adenosine uptake
(234), has been found to be greater in endurance athletes than
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in sedentary subjects, indicating a greater flow reserve. In lon-
gitudinal studies, a period of endurance training has accord-
ingly been shown to increase coronary flow reserve in healthy
individuals (456) and patients with coronary disease (158).
Resistance arteries
In contrast to conduit arteries, resistance artery dimensions
cannot be directly measured but have instead been estimated
from measurements of maximal flow changes in response to a
period of ischemia (112, 404, 421). The method estimates the
dimensions of the whole resistance vasculature and assumes
that absolutely maximal flow capacity is achieved after the
ischemic period and that there therefore is no functional limi-
tation to the measurements. This assumption could leave some
uncertainty as to whether maximal flows actually have been
achieved in all studies. However, evidence has been provided
for that the training-induced increase in maximal response
with this method is not necessarily paralleled by an increased
capacity of vasodilator systems (140, 145) and the response
does not appear to be affected by sympathetic drive (421).
Endurance training has been observed to increase the max-
imal vasodilator capacity, as assessed by ischemia with or
without added exercise. Sinoway and coworkers reported a
greater peak vasodilator response in the dominant arm of
tennis players (402) and a maximal vasodilator response has
been described after a period of forearm training in previously
untrained individuals (140, 143, 403). In the leg vasculature,
a higher maximal flow capacity was observed in endurance
trained than in sedentary individuals (407).
In laboratory animals, not only the dimension but also the
number of arteries and arterioles can be directly assessed by
methods including vascular casting and immunohistochemi-
cal differentiation of blood vessels. By use of vascular casting,
Laughlin and co-workers compared the effect of endurance
training and interval sprint training on the number of arterioles
in skeletal muscle groups of different fiber types in rats (246).
Their data showed that not only both endurance and sprint
training-induced growth of smaller arterioles but also that
growth differed depending on fiber type. Based on their find-
ings, the authors concluded that arteriolar growth occurred in
the muscles mainly used during the training, that is, endurance
training primarily leads to arteriolarization in oxidative and
fast oxidative glycolytic fibers (246). The authors also specu-
lated that the increased arteriolarization after endurance train-
ing (246) could be a contributing factor for their previously
observed 50% increase in flow capacity as assessed by differ-
ent levels of perfusion pressure (248). It may be mentioned
that fiber-type specific adaptations in the microvasculature in
rats are not so easily translated into humans as much of human
locomotor muscle, including the most commonly examined
vastus lateralis muscle, has a less uniform distribution of fiber
types (259).
Coronary arteriolar dimensions have also been shown to
be increased with endurance training. In a study on pigs, the
numerical and length densities of coronary arterioles were
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Cardiovascular Effects of Endurance Training
increased after a 12-week period of endurance training (44)
and, in rats, a higher cast weight of coronary arterioles was
observed after a period of endurance training (186).
Effects of training on arterial wall thickness
Most studies on the effect of endurance training on wall thick-
ness suggests that wall thickness is reduced with training both
in the forearm and leg (90,372,373,427) although an increased
arterial wall thickness in parallel with an increase in arterial
diameter has been reported (389).
Exercise training that induces large increases in blood
pressure such as heavy load resistance training, is likely to
have an impact on the arterial wall thickness similar to that
observed with hypertension (302). Data on the effect of resis-
tance training on arterial dimensions is sparse (34) but it has
been shown that resistance training increases wall thickness
without an equivalent effect on diameter leading to a higher
wall thickness to diameter ratio (389).
A functional consequence of a change in wall thick-
ness is a change in compliance. Several studies have
shown that endurance training increases arterial compliance
(53, 229, 284) whereas strength training can reduce arterial
compliance (31). However, alterations in arterial compliance
with training may also be related to changes in the wall com-
position (214, 274). Functionally, an improved compliance in
the large elastic arteries dampens the pulse pressure and is
important for maintaining flow high in the diastolic phase
also at high stroke volumes (the windkessel effect) (119).
Hemodynamic signals affecting arterial remodeling
An important hemodynamic variable for the increase in lumi-
nal diameter of arteries is shear stress (240, 335, 440). Shear
stress is the frictional force on the endothelium applied by the
blood as it flows through the vessel. Shear stress is elevated
when blood flow increases without a compensating change in
vessel diameter. In particular in smaller resistance vessels an
increase in shear stress will induce formation of vasodilators
leading to increased arteriolar diameter that neutralizes the
shear stress. However, despite this dilatory effect, shear stress
is a central signal for vascular remodeling at all levels of the
arteriolar tree. The clearest evidence for shear stress being an
important factor in expansion of the luminal diameter stems
from animal studies showing that interventions such as arterial
ligation with arteriovenous shunting, leading to increased flow
through the collateral arteries, results in a profound increase
in arterial diameter of these arteries (101, 386).
The shear stress induced enlargement of arteries is likely
to, at least in part, be mediated by NO. Shear stress leads
to both an acute increase in NO formation (374) and an
upregulation of endothelial nitric oxide synthase (eNOS)
(24, 440, 458). Inhibition of NO has been reported to abolish
both shear stress induced increase in carotid artery diameter
(435) and the exercise training-induced increase in collateral
flow in skeletal muscle (265). NO in turn interacts closely with
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vascular endothelial growth factor (VEGF) which is known to
be important in arteriogenesis (263). The interaction between
NO and VEGF is bidirectional; NO promotes VEGF expres-
sion (82,128,216) but VEGF can also promote NO formation
(304,328). It should, however, be emphasized that, in addition
to VEGF and NO, a vast number of compounds are affected
by shear stress and several of these may influence arterial
growth (96, 459).
Arterial wall thickness, has been reported to be dependent
on vasoconstriction (21, 94), increased sympathetic influence
(89), and changes in transmural pressure (112, 422). Trans-
mural pressure, which is the difference between the pressure
inside and outside of the vessel, is elevated with increased
blood pressure. Although systolic arterial blood pressure is
increased during endurance exercise, the increase is limited
and the effect on diastolic and mean arterial blood pressure is
small (62). In contrast, high load resistance exercise leads to
pronounced blood pressure changes, in particular resistance
exercise with large muscle groups during which systolic blood
pressure can exceed 300 mmHg. Severe resistance training
may also lead to permanent elevations in resting blood pres-
sure (389) which could contribute to increased vascular wall
thickness. It has been proposed that a more chronic increase
in blood pressure may have a greater impact on arterial wall
thickness compared to the transient increases that occur dur-
ing exercise (147).
To conclude, existing studies clearly show that exercise
training can modify the structure of larger arteries with the
most noticeable change being an increased luminal diameter
and a reduced wall thickness in response to endurance
training. An additional adaptation is an increase in the size
of the arteriolar tree. The stimulus for an increased vascular
diameter and arteriolar growth is thought to be primarily an
increase in shear stress. The functional consequence of an
increase in arterial diameter is reduced resistance during high
levels of perfusion, whereas changes in wall thickness and
wall composition have implications for vascular compliance.
Peripheral Adaptations to
Exercise Training
The effect of training on blood flow responses to
submaximal and maximal exercise
During exercise, blood flow to skeletal muscle can increase
up to almost 100-fold from rest to accommodate the increased
demand for oxygen by the contracting muscle. This elevation
in blood flow is achieved by an increased cardiac output in
combination with an enhancement in vascular conductance in
the active muscle. The increase in cardiac output upon initia-
tion of exercise is mainly driven by an increase in sympathetic
activity, which also induces an increase in vasoconstrictor
tone in most organs. In the active muscle, the increased sym-
pathetic vasoconstriction is overcome by local formation of
a number of different vasodilators but also by sympatholytic
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Comprehensive Physiology
compounds that directly reduce the effect of the sympathetic
activity. The below sections discuss how training may alter
exercise hyperemia and the mechanisms underlying vasodi-
latation in skeletal muscle.
Blood flow at submaximal workloads
Blood flow to the muscle during submaximal exercise has
been shown to be either unaffected (26, 315), reduced
(228, 315, 339), or even increased with exercise training
(28, 237). The discrepancy between findings is not clear but
may partly reflect the use of different subject groups. In the
study by Nyberg et al. (315) it was found that blood flow
during submaximal exercise performed at the same abso-
lute workload was reduced in normotensive subjects whereas
it was unaltered in hypertensive subjects after 8 weeks of
endurance training. Similarly, the study by Beere and co-
workers reported unaltered submaximal blood flows after
training in young but higher submaximal flows after train-
ing in aged (26). It appears plausible that subjects that have
impaired submaximal blood flows at the onset of training may
experience improvements in vasodilator capacity that cancel
out the peripheral adaptations leading to reduced submaximal
blood flows.
One frequently observed outcome of endurance training,
that likely affects the magnitude of blood flow to the muscle
during submaximal exercise, is an increased a-v O2 extrac-
tion, which in part occurs as a result of an increased cap-
illarization and thereby improved oxygen diffusion capacity
(220, 233, 380) (Fig. 4). Another training-induced adaptation
that may influence the level of blood flow to the active muscle
is an improved distribution of flow within the active limb.
Improved flow distribution may result from a more optimal
vascular architecture or a more precise neural control of blood
flow, with a consequent smaller portion of the blood being
distributed to nonactive muscle (380, 381). An improved dis-
tribution of flow is not easily determined but studies using
positron emission tomography indicate that endurance trained
individuals have less inhomogeneous blood flow distribution
during exercise (219, 220). Very low femoral venous oxygen
levels during maximal exercise have been observed in aged
life-long endurance trained individuals (Mortensen and Saltin,
unpublished observation) and although there may be several
explanations for this observation, the possibility of an opti-
mized microvascular architecture combined with improved
flow distribution is intriguing.
Maximal blood flow
It has long been known that endurance training leads to an
increase in exercise-induced maximal perfusion of skeletal
muscle (35, 255, 378). The earlier determinations were con-
ducted with xenon clearance methods during cycling exer-
cise and although they revealed a higher level of maximal
blood flow in trained compared to untrained individuals the
overall blood flow levels were unrealistically low (62, 255).
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Comprehensive Physiology Cardiovascular Effects of Endurance Training

(A) 3.0 160

Submaximal intensity

a-vO2 difference (ml L–1)

140
Blood flow (L min–1)

2.5

120

2.0 100

0.0 0

(B)
10 180
Maximal intensity
Blood flow
a-vO2 difference 160

a-vO2 difference (ml L–1)

8
Blood flow (L min–1)

140

6
120

4 100

0 0
Immobilized Untrained Trained

Figure 4 Femoral arterial blood flow and arterio-venous O2 difference during submaximal (A)
and maximal (B) single leg knee-extensor exercise with a previously immobilzed leg, untrained
and trained leg. Immobilization lasted for 2 weeks and was achieved by casting. Blood flow was
determined by ultrasound Doppler methodology, arterio-venous oxygen extraction was obtained
by measurements of oxygen content in blood drawn simultaneously from the femoral artery and
femoral vein. Adapted from (292) and (298) with permission of the American Physiological Society.

In the 1980s, Saltin and Andersen developed the one leg knee
extensor model that allowed for the determination of blood
flow to a limited muscle mass (7). A particularly useful aspect
of this model was that the active muscle mass could be defined
and that exercise with such a relatively small muscle mass
imposed no limit on the central capacity of healthy individ-
uals, thus the true maximal perfusion capacity of the muscle
could be more correctly determined. Use of this model, com-
bined with the thermodilution method for the determination
of blood flow (9), revealed maximal blood flow levels of 250
to 300 mL 100 g min−1 (9, 217, 354) which were evidently
greater than those previously reported for skeletal muscle
in humans (35, 255). Measurements of maximal perfusion
capacity in trained individuals with use of the one leg model
have shown a higher maximal perfusion capacity in well
trained than in untrained individuals (36, 353). One of the
limitations in comparing skeletal muscle blood flow during
maximal exercise in untrained versus trained individuals is
that the work capacity and the maximal limb oxygen uptake
of the trained individuals commonly is greater than that of the
untrained individuals (9, 233). As blood supply to the muscle
during maximal one-leg exercise is unlikely to be limiting
(9, 370), the higher blood flow in the trained would be a con-
sequence of the greater work output rather than a reflection
of maximal perfusion capacity.
Nevertheless, a greater perfusion capacity in trained mus-
cle is a likely outcome of aerobic training as evidenced by
greater maximal blood flows in endurance trained animals

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Cardiovascular Effects of Endurance Training
(247-249,397). The advantage in animal models compared to
the human model is that flow capacity can be assessed more
directly, by determination of maximal perfusion achieved
through increases in perfusion pressure, thus without influ-
ence of a change in performance. On the other hand, the lim-
itation with this method is that it primarily determines struc-
tural adaptations and not adaptations in vasodilator capacity.
As described in more detail below, similar kinds of mea-
surements have been performed in humans by use of brief
periods of ischemia alone or ischemia combined with exer-
cise to reach maximal perfusion capacity (329,402,421). Data
from such interventions in humans (143,402,407) confirm the
direct measurements in animals of greater maximal perfusion
in trained muscle.
The effect of training on flow-mediated
vasodilatation
The response in blood flow during exercise can be considered
the most functionally relevant test of vascular function, as it
examines the combined effect of a large number of regulatory
systems in an integrated response. Nevertheless, other vascu-
lar function tests, such as reactive hyperemia, flow-mediated
dilatation (FMD) and infusion of vasodilators are useful in that
they test mainly one vasodilating mechanism and the effect
or role of only one or a few vasodilator compounds. Such
tests therefore allow for more specific insight into vasoregu-
latory mechanisms than exercise and particularly FMD has
been proven useful as predictor of cardiovascular disease
(142). FMD is commonly measured in the brachial artery
and assessed as the change in vessel diameter that occurs
after a period of forearm occlusion induced by use of a cuff
(57). A large number of studies have been conducted in which
the effect of training on FMD has been evaluated in different
populations with an emphasis not only on individuals at risk
for cardiovascular disease (142), but also in healthy young
individuals (309, 409). Cardiovascular risk groups generally
experience marked improvements in FMD with exercise train-
ing (426) whereas the effects are less clear in young healthy
controls (146). As with other cardiovascular adaptations, an
important mechanism underlying an improved FMD response
with training is the exercise-induced shear stress signaling
(433) which is a stimulator of improved endothelial function
through an upregulation of vasodilators including NO (50).
Control of exercise hyperemia
Exercise hyperemia is a highly complex and well regulated
process that involves sympathetic vasoconstriction, an inte-
gration of a large number of vasodilator systems as well
as several modes of activation of these systems (Fig. 5).
During exercise the increased sympathetic activity causes
arteriolar constriction and in the active muscle effective
amounts of vasodilators have to be formed to overcome and
exceed this constriction to enable sufficient oxygen delivery.
Our understanding of precisely how skeletal muscle blood
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Comprehensive Physiology
flow is regulated is not complete. A number of mecha-
nisms and compounds have been identified and proposed
to play a role but exactly how the systems are integrated
and their relative importance and roles remain somewhat
unclear. Out of the mechanisms and compounds identified,
several induce their effect via sensors or receptors located on
the endothelium, resulting in the formation of vasodilators.
Such endothelial-dependent mechanisms include flow (shear
stress)-induced vasodilatation and vasodilatation induced by
chemicals such as ATP and adenosine. Apart from endothe-
lial cells, cellular sources of vasodilator compounds dur-
ing exercise include erythrocytes and skeletal muscle cells.
Skeletal muscle cells produce vasodilators such as NO, ATP,
and adenosine (176, 177) whereas erythrocytes have been
shown to release the vasodilators ATP (105) and NO (401) in
response to oxygen desaturation of the hemoglobin molecule.
This latter mechanism is highly attractive as it provides
a direct link between oxygen and vasodilatation; however,
the physiological importance of this mechanism in humans
remains unclear.
An important mechanical signal in the cardiovascular sys-
tem is shear stress. As should be evident from other sections
in this review, shear stress has a range of acute and long
term effects on the vasculature and changes in shear stress
levels due to inactivity or activity markedly alters the phe-
notype of endothelial cells and affects vascular function and
vascular growth, (96, 433, 459). The acute effect of increased
shear stress is an increase in the formation of vasodilators
including NO, prostacyclin, and endothelial-derived hyper-
polarizing factors (EDHF) (50), but NO may be the most
important component (141). The role of shear stress for exer-
cise hyperemia is unclear but it is more likely that shear stress
has a role in fine tuning rather than in regulation of the overall
magnitude of blood flow.
Another mechanism in the control of blood flow to the
working muscle is conducted vasodilation. Conducted vasodi-
lation is a process in which the signal for vasodilatation trav-
els up- and downstream, along the vascular wall, either in the
endothelium or the smooth muscle cells, via gap junctions
(20, 396). This mechanism is important for coordination of
flow as it allows vasodilatation to occur in the larger upstream
vessels that do not necessarily experience the chemical or
mechanical stimuli that are present in proximity of the work-
ing muscle fibers. It has been clearly demonstrated that con-
traction of muscle fibers induces conducted vasodilation in
animal models, supporting a functional role of this mecha-
nism in the exercising skeletal muscle (67, 305).
An additional vasodilator mechanism is the myogenic
response, which is the response of smooth muscle cells to
changes in transmural pressure that occur with a change in
blood pressure. The myogenic response is known to exist
in skeletal muscle arterioles, especially in smaller arterioles
(85), and it has been shown that vasodilatation induced by
mechanical compression, as would take place during con-
traction, occurs in part through a myogenic response (64).
However, as such, the myogenic response may not be of great
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Comprehensive Physiology Cardiovascular Effects of Endurance Training

Muscle
Conducted contraction/
vasodilation metabolism

Endothelial Functional
mediated dilation sympatholysis

Mechanically Chemically Cellular

induced induced sources

Endothelial cell Skeletal muscle cell Red blood cell

Adenosine Adenosine ATP

ATP ATP NO
NO NO
Prostanoids ROS
EDHF
Endothelin-1
ROS

Smooth muscle cell

Figure 5 Regulation of skeletal muscle blood flow during exercise. Several vasoactive mechanisms are involved
in the regulation of skeletal muscle blood flow during exercise and together these mechanisms secure a highly
precise oxygen delivery for the energy production required for the contractile work of the muscle. The vasodilator
mechanisms include endothelial dependent vasodilatation which can be induced both by mechanical influence,
primarily via shear stress, but also chemically via compounds such as ATP and adenosine. In response to the
contractile work, skeletal muscle cells can produce and release vasodilator compounds including nitric oxide
(NO) and ATP. NO and ATP can also be produced by red blood cells in response to off-loading of oxygen
from the hemoglobin molecule which occurs in the arterioles and capillaries. Coordination of blood flow in the
microvascular system is facilitated by retrograde conducted vasodilation. In conducted vasodilation an electrical
signal and a calcium wave travel in retrograde direction leading to vasodilatation in upstream arterioles. Finally,
specific compounds such as ATP may reduce the efficacy of sympathetic activity in the skeletal muscle arterioles,
thereby reducing the constrictive effect. ATP: Adenosine 5′ triphosphate, NO: nitric oxide; ROS: reactive oxygen
species; EDHF: endothelial-derived hyperpolarizing factor.

importance for control of skeletal muscle blood flow during
exercise.
It should be mentioned that, although most vasodilator
mechanisms can be activated from the luminal side of the
blood vessels, compounds on the interstitial side, such as
those formed by the skeletal muscle, are also likely to be
important in blood flow control. Vasodilators present in the
muscle interstitium may induce their effect by direct action
on the smooth muscle cells or via endothelial cells, either
at the capillary level inducing conducted vasodilation, or at
the arteriolar level through endothelial cell protrusions (384).
Several vasoactive compounds have been shown to increase
in the interstitium with exercise including adenosine, ATP,
prostacyclin, and NO (116, 176). Out of these compounds
adenosine, prostacyclin, and NO can induce vasodilatation
by direct action on the smooth muscle cells. Interstitial ATP
can induce vasoconstriction via P2X receptors on the smooth
muscle cells or, alternatively, induce vasodilatation by acting
on P2Y receptors on the endothelial cells (48). Animal experi-
ments have suggested that the vasodilatory effect of interstitial
ATP is stronger than its constrictive effect (93, 313).
In summary, skeletal muscle blood flow during exercise
is regulated by a balance between, on one hand, primarily
sympathetic vasoconstriction and, on the other hand, sev-
eral vasodilating mechanisms leading to the formation of
endothelial-dependent and endothelial-independent vasodila-
tors. In addition, as further described below, metabolic
modulation of the effect of the sympathetic nervous activity,
so-called functional sympatholysis, is likely to be a central
regulatory mechanism in exercise hyperemia.
Effect of endurance training on vasodilator
capacity and vasoconstrictors
One of the most well studied vasodilator systems in skeletal
muscle tissue is NO (Fig. 6). The functional role of NO for

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Cardiovascular Effects of Endurance Training
Figure 6 The effect of endurance training on vasodilators and vaso-
constrictors involved in the regulation of skeletal muscle blood flow.
Skeletal muscle blood flow regulation is brought about by a balance
between on one hand sympathetic vasoconstriction and other vaso-
constrictors such as endothelin 1 (ET-1) and thromboxane (TXA2 ) and
on the other hand vasodilators formed in the active muscle, of which
nitric oxide (NO) and prostacyclin (PGI2 ) appear to be central. Another
important aspect in skeletal muscle blood flow regulation is the sub-
stantial interaction between vasodilator systems and compounds. For
example, ATP and adenosine can mediate vasodilatation via activation
of receptors on the endothelial cells resulting in the formation of NO and
PGI2 . NO and PGI2 in turn interact in a redundant manner so that when
one is inhibited the other system can compensate. The effect of train-
ing on the formation of vasodilators and constrictors (marked by blue
arrows) has not been fully clarified and the attempt to illustrate changes
in this figure is tentative. Studies show that the concentrations of NO and
prostacyclin in plasma and the muscle interstitium are either enhanced
or remain unaltered at rest and during exercise. Adenosine and ATP
levels in the muscle interstitium may increase with training, however, in
parallel, the vascular sensitivity to nucleotides is reduced. On the con-
strictor side, ET-1 and TXA2 have been shown to be reduced in plasma
at rest whereas plasma noradrenaline is reduced during exercise indi-
cating an attenuated sympathetic drive. ATP = Adenosine 5’triphos-
phate, ADO = adenosine; PGI2 = prostacyclin; NO = nitric oxide; NE
= Noradrenaline, ET-1 = endothelin-1, TXA2 = thromboxane A2 . p and
i in figure beside blue arrows specify that changes were observed in
plasma and muscle interstitium, respectively.
exercise hyperemia has been determined by use of NO block-
ade during exercise. Such studies have shown that removal
of NO production by infusion of an NOS inhibitor does
not alter leg blood flow (118, 344), whereas in the forearm,
NOS inhibition has none or a modest effect on steady-state
exercise hyperemia (131, 390, 398) but a more pronounced
effect on the rapid rise in blood flow at onset of exercise
(55, 56). Several studies have, moreover, found a lowering
of blood flow with combined inhibition of NOS with either
inhibition of cyclooxygenase (41, 173, 291) or inhibition of
cytochrome P450 2C9, an enzyme producing the endothe-
lial derived hyperpolarizing factor 11, 12, eicosatrienoic acid
(184). Based on existing data, it has been theorized that NO is
important for exercise hyperemia, but not obligatory as other
systems may compensate for NO when the formation of NO
is impaired. For a more complete description of the interac-
tion and redundancy of vasodilators, the reader is referred to
reviews specifically addressing this topic (177).
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Comprehensive Physiology
A training-induced enhancement in NO availability could
potentially be brought on by several mechanisms including
increased eNOS protein, increased eNOS activity by changes
in phosphorylation status, reduced eNOS uncoupling and
reduced removal of NO by reactive oxygen species (114).
These mechanisms are described below.
eNOS expression
A large number of human (66,117,161) and animal (251,277)
studies have shown a higher level of eNOS protein in skele-
tal muscle tissue and blood vessels after a period of exercise
training. Through detailed studies on eNOS expression in
the arteriolar bed of trained rats, McAllister and co-workers
(276) demonstrated that training-induced alterations in eNOS
differed according to fiber type and also concluded that the
upregulation of eNOS occurred primarily in muscles in which
training had induced a flow response. This proposition fits well
with the documented importance of shear stress in upregula-
tion of eNOS (136, 352). It should be noted that exercise
training also has been shown to increase levels of neuronal
NOS (nNOS) (135, 314, 315, 408). nNOS, which is located
in large amounts within the skeletal muscle fibers, may con-
tribute to vascular control, in part through its role in functional
sympatholysis in rodents (430).
eNOS activation
Findings on the effect of training on the basal state of acti-
vation of eNOS, as assessed by changes in eNOS phospho-
rylation status or direct measurements of activity in skeletal
muscle, have not been consistent. Some studies in humans
(59, 135, 315) and rodents (278, 436) have shown no effect
of exercise training either on basal vascular eNOS phos-
phorylation or activity. However, an increased eNOS activity
after training has been reported in skeletal muscle of young
(165) and aged (408) rodents. Moreover, immunohistochem-
ical analysis of eNOS phosphorylation has shown a reduction
in the basal and exercise-induced eNOS ser1177 phosphoryla-
tion after training (66). The reason for these discrepancies in
findings is not clear.
eNOS uncoupling
eNOS is a homodimeric enzyme which can be uncoupled to
monomers due to factors such as increased oxidative stress and
reduced availability of the cofactor tetrahydrobiopterin (BH4)
(114). Instead of forming NO, the eNOS monomer produces
the reactive oxygen species, superoxide, thereby resulting in
not only a reduced formation of NO but also an increased for-
mation of superoxide anions that can react with and remove
NO (113). A direct assessment of eNOS uncoupling by West-
ern blot analysis in humans before and after a training period
has been conducted in skeletal muscle samples of normoten-
sive and hypertensive individuals (315). The study showed
that the content of eNOS monomers to total eNOS in skeletal
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muscle tissue was lower after training in both groups of sub-
jects, reflecting a reduced degree of uncoupling. In addition,
indirect evidence for eNOS uncoupling has been reported in
rodents (399). The authors demonstrated that the availability
of BH4 was restored in aged rodents with exercise training
concomitant with an improved flow stimulated NO availabil-
ity in soleus arterioles (399). Functionally, eNOS uncoupling
could have a relatively large impact on NO availability and
further studies on the effect of training on eNOS uncoupling
are clearly warranted.
Removal of NO by ROS
Exercise training may enhance NO bioavailability by reduc-
ing the presence of ROS and thus lowering scavenging of
NO by ROS, at least in the elderly. In elderly individuals,
the bioavailability of NO is seemingly lower than in young,
an effect that, at least in part, may be related to an increased
presence of ROS (79, 121, 231, 417). Comparisons between
physically active and sedentary aged and young have shown
that NO availability, as assessed by an improved response to a
vasodilator stimulus after infusion of the antioxidant ascorbic
acid, was improved in sedentary aged individuals with little
effect seen in young and trained elderly (121, 417). In a study
determining NO metabolites in plasma and muscle intersti-
tial fluid in sedentary and lifelong trained aged individuals,
infusion of the antioxidant n-acetylcysteine (NAC) revealed
a greater elevation in NO metabolite concentrations in the
untrained than in the trained individuals (314). These find-
ings suggest that exercise training reduces the removal of NO
by ROS, potentially by improving the endogenous antioxidant
defense (336). Interestingly, in contrast to the findings in the
forearm (79, 231, 417), the improved NO availability in the
aged sedentary group with NAC infusion was not paralleled
by improved exercise hyperemia in the leg, suggesting that
the increased presence of NO had little functional influence
(314). In the discussion on the removal of NO by ROS it
should, nevertheless, be emphasized that an appropriate bal-
ance between NO and ROS appears essential for adaptation
to training and function in the vascular system as evidenced
by training-induced enhancements in NADPH oxidase (135)
and evidence for the importance of ROS in vascular function
(135, 399, 400).
Overall, evidence suggests that endurance training can
improve NO availability by reducing NO removal by ROS,
presumably via improved antioxidant defense or reduced ROS
formation, although this may primarily be evident in aged
individuals or individuals with compromised vascular func-
tion (121, 316).
Functional role of NO in trained versus
untrained individuals
A few studies have assessed the functional role of NO in
trained versus untrained subjects through studies of NO block-
ade. The vasodilator response to ACh and bradykinine has
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Cardiovascular Effects of Endurance Training
been shown to be more markedly improved in exercise trained
than in sedentary muscle (125,181,301). Nyberg et al. showed
that combined NOS and COX inhibition reduced exercise
hyperemia more after 8 weeks of spinning training in nor-
motensive individuals suggesting that the role of NO and
prostanoids was lower after training (315). Accordingly, the
hyperemic response to passive movement of the lower leg,
which is induced by shear stress and almost fully NO depen-
dent (287), appears to be lower in young trained compared
to untrained individuals (Nyberg, Bangsbo, Hellsten, unpub-
lished observation) whereas in aged training was shown not
to alter the magnitude of hyperemia during passive move-
ment (135).
Based on existing data on the effect of training on eNOS
and NO availability and function, it may be concluded that
endurance training can lead to an improvement in the avail-
ability of NO in skeletal muscle, in part by increased forma-
tion of NO and in part by reduced removal of NO via ROS.
Evidence point at that increased formation of NO may be the
result of increased eNOS expression and increased eNOS acti-
vation via shear stress or chemical (e.g., ATP or adenosine)
influence. The functional consequence of improved NO avail-
ability may be more evident in the forearm than the leg vas-
culature but also most prominent in individuals with impaired
vascular function.
Prostaglandins
Vasoactive prostaglandins include the vasodilators prostacy-
clin and prostaglandin E2 and the vasoconstrictor thrombox-
ane A2. There has been much less focus in the literature on
the role of prostaglandins than on NO for control of exer-
cise hyperemia, however, prostacyclin is a mediator of both
mechanical and chemical signals in the vasculature including
shear stress (199) and ATP and adenosine induced vasodi-
latation in the leg (290, 294) with a limited effect evident
in the forearm (78, 362). As described above, prostacyclin
has been proposed to interact closely with NO in a manner
where prostacyclin can compensate for a lack of NO and vice
versa (40, 291). Studies have shown that a period of exer-
cise training increases the protein concentration of prostacy-
clin synthase and COX-1 in skeletal muscle tissue (135, 175)
although this has not been observed in all studies (161). In
animal studies, training-induced improvements in endothelial
dependent vasodilatation via bradykinine and acetylcholine
are partly dependent on prostaglandins (86, 87). Moreover,
in individuals with essential hypertension, training enhances
the increase in muscle interstitial prostacyclin in response to
adenosine infusion (175) and improves the balance between
basal prostacyclin and thromboxane levels in the muscle inter-
stitium (161). Therefore, although relatively limited data is
available on the effect of training on the prostaglandin system,
evidence point in the direction of that this system contributes
importantly to the training-induced improvement in vascular
adaptations.
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Nucleotides
ATP
ATP has been proposed to hold several roles in muscle blood
flow regulation. ATP in plasma binds to P2Y purinergic recep-
tors on the endothelium (74), most likely P2Y2 receptors,
leading to formation of NO, prostaglandins, and possibly
other unidentified vasodilators (330). ATP can also induce
a propagated response, initiated from the smallest microves-
sels and capillaries, leading to upstream vasodilatation (105).
In addition, ATP has a sympatholytic effect (365) and may
induce vasodilatation through hyperpolarization of the vascu-
lar cells (77). The functional role of ATP has been proposed to
be related to distribution of microcirculatory flow more than
to the magnitude of flow to the muscle (412).
ATP increases both in plasma and in the muscle intersti-
tial fluid during acute exercise (176, 297). In the circulation,
ATP may originate from erythrocytes, endothelial cells or
platelets, although erythrocytes appear to be a primary source
(412). It has been well documented that erythrocytes release
ATP in response to a reduction in oxygen saturation of the
hemoglobin molecule, a mechanism that occurs primarily in
the smallest arterioles and the capillaries (411). There is also
evidence for that compression of erythrocytes causes release
of ATP (105). It should be noted that in patients with cys-
tic fibrosis, erythrocytes lack the capacity to release ATP, yet
exercise hyperemia is similar in magnitude to that of controls
(391). This observation would suggest that ATP originating
from erythrocytes is not obligatory for bulk flow to the muscle;
however, it does not exclude a role in flow distribution.
In the muscle interstitium, ATP is thought to originate
primarily from the contracting skeletal muscle although the
underlying mechanism is not completely clarified. In vitro
studies have provided evidence for that ATP may be released
from skeletal muscle cells via pannexin-1 hemi channels (51)
and the cystic fibrosis transmembrane conductance regula-
tor (438). Measurements of ATP in the muscle interstitium
have revealed inconsistent findings. In aged men, ATP levels
have been reported to be higher in life-long trained compared
to sedentary men (295) whereas in hypertensive individuals
reduced interstitial ATP levels were observed after training
(161). Moreover, in young healthy men, a period of immo-
bilization by casting of one leg was shown to reduce the
exercise-induced increase in inerstitial ATP levels (292). So
far, no studies have addressed the effect of exercise training
on the specific mechanisms of ATP release from erythrocytes
in vitro.
In the muscle interstitium, ATP may actually induce vaso-
constriction by direct action on purinergic P2X1 receptors
located on the smooth muscle cells (48). It has, however,
been shown in laboratory animals that superfusion of skele-
tal muscle with ATP, which would correspond to increased
ATP in the interstitium, induces vasodilatation (93,313). Inhi-
bition of NO and prostaglandin formation abolishes ATP-
induced vasodilatation in this model suggesting that the effect
of interstitial ATP is mediated by the formation of these
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Comprehensive Physiology
vasodilators, most likely via purinergic receptors on the
endothelium (313). Somewhat unexpectedly, endurance train-
ing leads to a reduced sensitivity to arterially infused ATP
(293), whereas immobilization of the leg leads to an increased
sensitivity to infused ATP (292). This may seem counterintu-
itive; however, it may suggest that the relative importance of
the different vasoactive compounds can change with training
status.
Adenosine
Adenosine is a degradation product of ATP that binds to
P1 purinergic receptors whereby NO and prostaglandins are
formed (348,406). In humans, the concentration of adenosine
in plasma does not increase during exercise, which probably
is related to a very brief half-life of this purine. In the muscle
interstitium, the adenosine concentration does increase with
exercise, to some extent in relation to exercise intensity (176).
Nonspecific inhibition of adenosine receptors lowers blood
flow to exercising muscle by about 15% to 20% (294,343) pro-
viding evidence for a functional role of adenosine in exercise
hyperemia, although there are individual differences as evi-
denced by a negligible effect of adenosine receptor blockade
on exercise hyperemia in a fraction of the population (272).
Limited data exist on training and the adenosine sys-
tem. In hypertensive individuals, training has been shown
to result in an increased exercise-induced muscle intersti-
tial adenosine concentration whereas no effect was observed
in a matched group of normotensive individuals (175). The
vasodilator response to adenosine after a period of training
has been reported to be lowered in the human leg (175) and
either unaffected (241) or enhanced (87) in animals. Further
studies are needed to clarify these divergent findings.
An overall conclusion from existing data is that training
can increase the exercise induced ATP and adenosine forma-
tion and reduce the sensitivity to ATP and adenosine. It is
clear that nucleotides are important for the control of skeletal
muscle blood flow, however, the effect of exercise training on
the functional role of ATP and adenosine remains uncertain.
EDHF
The concept of EDHF was originally derived from the finding
that a fraction of the vasodilatory response to a vasodilator
such as ACh, is still present when NO and prostaglandin for-
mation is blocked (49). The remaining vasodilatation related
to hyperpolarization is defined as EDHF (49, 111). EDHF
has been identified as multiple compounds, where the iden-
tity differs between tissues and vessel size. In skeletal mus-
cle, hydrogen peroxide and eicosatrienoic acids (38,108,256)
have been identified as EDHFs. No human studies have doc-
umented an effect of endurance training on the role of EDHF
for vascular function, however, in rodents, EDHF has been
implicated in training-induced improvements in endothelial-
dependent dilation in cardiac (148, 285) and skeletal muscle
(149).
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Endothelin-1, thromboxane, and angiotensin II
Endothelin-1 is a circulating vasconstrictor thought to be of
importance in particular in pulmonary hypertension, kidney,
and metabolic syndrome (383). Individuals with metabolic
syndrome commonly have elevated levels of endothelin and
there are also indications that endothelin bears a relation-
ship to age (317). In healthy young and old individuals,
endothelin receptor A/B blockade or specific receptor A
blockade has been shown to increase exercise hyperemia
with a greater effect observed in aged (23, 428). Moreover, in
spontaneously hypertensive rats, treatment with a blocker of
endothelin receptor A has been shown to increase flow depen-
dent dilatation (203). Endurance training has a pronounced
effect on levels of endothelin-1 in plasma and endurance
training has been found to reduce endothelin-1 levels by up
to 30% (25, 270, 317, 319). Maeda and collaborators (269)
found that endothelin A and B receptor inhibition improved
carotid artery compliance in sedentary middle-aged and older
subjects and that this effect was abolished after regular physi-
cal activity in parallel with a lowering of plasma endothelin-1
levels. In animal studies, the effect of training on the func-
tional role of endothelin-1 is less consistent (91, 250). It is
not known whether the improved vascular function com-
monly observed with training is related to the reduction in
plasma endohelin-1 levels; however, it is likely a contributing
factor (428).
Thromboxane A2 is a vasoconstrictor formed in the
arachidonic acid pathway, a pathway that also produces
other prostanoids including the vasodilator prostacyclin. An
impaired balance between vasodilating and vasoconstricting
prostanoids is thought to be a contributing factor in the devel-
opment of vascular dysfunction in cardiovascular disease
(444). Limited evidence exist for the effect of exercise training
on the balance of vasodilating and constricting prostanoids in
humans but there are indications in the literature that exercise
training may improve the prostanoid balance toward more
vasodilators (161, 413).
Angiotensin II is also a vasoconstrictor that is considered
a central factor in vascular dysfunction (376) and, in individ-
uals with cardiovascular disease, exercise training lowers the
angiotensin levels in plasma (468).
Combined, existing data suggest that exercise training can
reduce vasoconstrictor levels, which may be a contributing
factor to the reduced peripheral resistance and the lowering
of blood pressure in cardiovascular disease states.
Exercise training and smooth muscle cell function
Smooth muscle cell sensitivity is in vivo assessed as vasodi-
lation in response to a compound that can relax the smooth
muscle cell without the presence of the endothelium. This
is often referred to as endothelial independent vasodilata-
tion. Experimentally, smooth muscle cell sensitivity is often
determined by use of an NO donor (e.g., sodium nitroprus-
side or nitroglycerin). Interestingly, most studies examining
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Cardiovascular Effects of Endurance Training
the effect of training on vascular function in humans and
laboratory animals have reported a lack of effect on smooth
muscle cell sensitivity to NO (88, 120, 436) although excep-
tions exist (242). It is nevertheless unlikely that improved NO
sensitivity is a primary mechanism behind training-induced
improvements in vascular function. Other compounds such
as adenosine and prostacyclin can also induce vasodilatation
through direct action on the smooth muscle cells, however, as
adenosine also acts via endothelial cells (318) and prostacy-
clin shows a strong interaction with NO (311) the interpreta-
tion of their direct effect on smooth muscle is difficult.
In animal models, exercise training has also been shown to
affect aspects such as calcium control (442) and the expression
and activity of potassium channels in vascular smooth muscle
cells (261, 464), but to date little evidence exists in humans.
Effect of Exercise Training on
Functional Sympatholysis
During exercise, sympathetic nervous activity increases
(5, 394) in both resting and contracting skeletal muscle
(163, 347, 414). In inactive tissues, the increase in sympa-
thetic drive causes vasoconstriction (32, 368). However, in
young healthy individuals the vasoconstrictor effect of an
increase in sympathetic nervous activity, induced by lower
body negative pressure (162, 447), or by an increase in nore-
pinephrine release from sympathetic nervous endings induced
by tyramine infusion (292, 295, 314, 364, 437), can be attenu-
ated or even abolished in skeletal muscle during contraction.
This phenomenon, termed functional sympatholysis (351), is
thought to allow adequate perfusion and oxygen delivery to
the contracting fibers (379). In accordance, inhibition of α-
adrenergic tone has been shown to disturb the distribution of
blood flow and oxygen extraction in contracting skeletal mus-
cle by increasing blood flow around especially inactive muscle
fibers (174). The mechanisms underlying functional sympa-
tholysis is thought to involve locally released substances that
modulate the postreceptor effect of norepinephrine binding to
α-receptors on the smooth muscle cells (379).
Although the first report of a contraction-induced
attenuation of sympathetic nervous activity was presented in
1937 (349), only a few studies have looked at the effect of
exercise training on functional sympatholysis. Remensnyder
and co-workers (351) demonstrated in 1962 in dogs that the
responsiveness of a vascular bed to adrenergic stimulation at
rest diminishes significantly with a small increase in oxygen
uptake. It was more recently shown in humans that following
an exercise bout, a blunting of sympathetic vasoconstriction
was evident in the skeletal muscle previously engaged
in exercise (299). This residual effect of acute exercise
indicates that exercise training is central for stimulating
the signaling pathways that are important for functional
sympatholysis. In accordance, data obtained from both longi-
tudinal (209, 292, 293) and cross-sectional (295) studies have
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3.0
Exercise
Exercise + tyramine
Blood flow (L min–1)
2.5
2.0
0.0
Immobilized Untrained Trained
Figure 7 Femoral arterial blood flow during knee-extensor exercise
without and with arterial infusion of tyramine (induces a release of nore-
pinephrine from sympathetic nerve endings) with a previously immobi-
lized, untrained, and trained limb. Immobilization lasted for two weeks
and was achieved by casting. Blood flow was determined by ultrasound
Doppler methodology, arterio venous oxygen extraction was obtained
by measurements of oxygen content in blood drawn simultaneously from
the femoral artery and femoral vein. Adapted from (292) and (295)
with permission.
provided strong evidence for that the ability for functional
sympatholysis is related to the training status of the skeletal
muscle (Fig. 7).
The mechanisms underlying the effect of training on func-
tional sympatholysis are still unresolved, but data obtained
from the human leg indicates that a reduced α-adrenergic
responsiveness may be important (293), whereas rodent data
suggest that functional sympatholysis is augmented through a
NO-dependent mechanism in an intensity-dependent manner
(209). In regard to the latter study, a more pronounced vaso-
constrictor effect of sympathetic stimulation was observed
in trained rats at rest. Since sympathetic stimulation elicited
the same vasoconstrictor response in the control and trained
animal during contractions, the augmented functional sym-
patholysis was a direct effect of the increased sympathetic
responsiveness detected at rest (209). Importantly, blood flow
and oxygen delivery is of paramount importance for skeletal
muscle performance, and the observation that similar sympa-
thetic stimulation elicited a comparable constrictor response
during contractions in the trained and untrained animals indi-
cates that the augmented functional sympatholysis may have
served to counteract the increased sympathetic responsive-
ness. Conversely, human data have provided evidence for
that the vasoconstrictor response to a similar release of nore-
pinephrine from sympathetic nerve endings with infusion of
tyramine during contractions is attenuated with exercise train-
ing (293, 295). Furthermore, NO has been shown to mediate
functional sympatholysis in rat skeletal muscle (431) and NO
has been suggested to play an important role in modulat-
ing sympathetic vasoconstriction in the microcirculation of
human contracting forearm muscle (59, 382). However, infu-
sion of a NO donor does not blunt sympathetic vasoconstric-
tion in the forearm of young men (363) and increasing NO
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Comprehensive Physiology
availability in older men with impaired functional sympa-
tholysis does not increase leg exercise hyperemia (295, 314).
Collectively, these observations indicate that NO may not
be essential for functional sympatholysis in humans and the
findings in the rat (209) may, therefore, be species specific.
As described previously, the concentration of ATP
increases in the plasma of the arterial inflow and venous
drainage of active skeletal muscle (139, 297), and when
infused, ATP can significantly blunt sympathetic α-adrenergic
vasoconstriction in young adults (230, 364). In accordance,
ATP released from erythrocytes has also been suggested to
contribute to the regulation of microvascular perfusion dis-
tribution in skeletal muscle (411). Although these findings
suggest that intravascular ATP may be an important medi-
ator of functional sympatholysis, no evidence for a causal
link between functional sympatholysis, intravascular ATP and
training status has been provided. During muscle contractions,
the concentration of ATP increases in the extracellular space
in proportion to the intensity of contraction (176, 260) and
interstitial ATP has been shown to induce vasodilatation in
skeletal muscle (313). The concentration of skeletal muscle
interstitial ATP during exercise is reduced with immobiliza-
tion (296) and increased in lifelong physically active men
(295). In agreement with these observations, a close coupling
also exist between the concentration of interstitial ATP and
the degree of functional sympatholysis (312). Taken together,
the level of interstitial ATP may be important for the degree
of functional sympatholysis and one mechanism underlying
the beneficial effect of exercise training on the modulation of
sympathetic nervous activity could potentially be an increase
in the concentration of skeletal muscle interstitial ATP.
Oxidative stress has been suggested to impair functional
sympatholysis in skeletal muscle of rat hindlimb and human
forearm (107). Since reactive oxygen species (ROS) scavenge
NO and thereby decreases the bioavailability of this vasoac-
tive substance (106,418), such an effect of oxidative stress on
functional sympatholysis is in congruence with the reported
role of NO for functional sympatholysis in the rat (431) and
human forearm (59,382). Exercise training effectively upreg-
ulates antioxidant systems in both blood and skeletal muscle
(133, 135, 137, 314, 316), allowing for a greater removal of
ROS which may contribute to the improved functional sympa-
tholysis in trained skeletal muscle. Evidently, more evidence
is needed to substantiate such an effect of training on ROS
handling and functional sympatholysis.
To summarize, contracting skeletal muscle effectively
counteracts the vasoconstrictor effect of an increase in sym-
pathetic nervous activity. The mechanisms underlying this
functional sympatholysis may involve locally released sub-
stances such as ATP and NO that modulate the postrecep-
tor effect of norepinephrine binding to α-receptors on the
smooth muscle cells. It should, however, be noted that species
and limb differences are likely to exist. The ability for func-
tional sympatholysis is to a large extent related to the training
status of the contracting skeletal muscle. This close associ-
ation between training status and the degree of functional
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sympatholysis could be an effect of a training-induced reduc-
tion in α-adrenergic responsiveness and/or changes in the ATP,
NO and antioxidant systems.
Capillary Growth in Skeletal Muscle in
Response to Training
The level of capillarization in skeletal muscle is highly impor-
tant for the functional capacity of the muscle, in particular
for endurance performance but also for performance during
shorter term exercise at high intensities. An increase in car-
diac output observed with endurance training, allows for an
enhanced perfusion capacity of the muscle during whole body
exercise at high to maximal aerobic intensities. Without a par-
allel enlargement of the microvascular network, the conse-
quent increase in velocity of the red blood cells would reduce
the time for gas exchange at the capillary site and lead to less
optimal conditions for oxygen supply and thus uptake in the
muscle tissue. Under these conditions, the improved cardiac
output would not necessarily be fully utilized. An increased
capillary volume is therefore an advantageous adaptation to
training, securing sufficient time for off-loading of oxygen
in the muscle. Importantly, the increased capillary density
will also improve the diffusion area and diffusion distance for
gasses, nutrients and metabolic waste products.
The importance of capillary density in skeletal muscle is
supported by the plasticity of the capillary network where
only a few days of muscle activity in rodents and less than
4 weeks in humans can induce increases in capillary den-
sity (83, 164, 210). It should be pointed out that, although
an increased capillary density is a critical adaptation to exer-
cise training, the specific distribution of capillaries within the
muscle is also an important factor for optimal oxygen supply
to the muscle (97).
Effect of endurance training on capillary growth
Endurance training is likely to be the most potent physiologi-
cal stimulus of capillary growth in skeletal muscle. In humans,
a number of studies on the effect of training on skeletal mus-
cle characteristics were originally conducted almost half a
century ago, when the skeletal muscle biopsy technique of
Bergstrom was introduced to the field of exercise physiol-
ogy (30, 223). One of the first studies examining the effect of
endurance training on capillarization in human muscle with
this technique was conducted by Andersen and Henriksson in
1977 (8). They showed that eight weeks of moderate intensity
cycle training in sedentary healthy young males, lead to an
approximate 40% increase in capillary density in the thigh
muscle (8). In general, the literature shows that, when previ-
ously sedentary, healthy individuals are subjected to periods
of 4 to 8 weeks of endurance training of moderate intensities
at between 60% and 80% of VO2max , an increase in capillar-
ization of between 10% and 40% is observed (190, 206, 232)
(Fig. 8). The difference in magnitude of capillary growth
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Cardiovascular Effects of Endurance Training
3.5
Untrained/moderately trained
Well-trained
3.0
2.5
Capillary-to-fibre ratio
2.0
1.5
1.0
0.5
0.0
0 weeks 4 weeks 7 weeks Cross-sectional
Figure 8 Capillary-to-fiber ratio in untrained (VO2max : ∼50 mL O2
min−1 kg−1 ) young men before (0 weeks) and after 7 weeks of exer-
cise training (7 weeks) and in trained (VO2max : ∼66 mL O2 min−1
kg−1 ) young men (cross-sectional). The 7-week training period consisted
of high-intensity interval training. Capillary number was obtained by
counting of immunohistochemically stained transverse muscle sections
cut from frozen muscle (m.v. lateralis) samples. Fitness level was deter-
mined by measurements of expired air during a graded cycle test to
exhaustion. Adapted from (210) and (201) with permission.
probably reflects factors such as the activity level of the sub-
jects prior to training, the efficacy of the training program
and training compliance. The efficacy of the training may be
related to the intensity and duration of training although the
importance of training intensity versus volume for capillar-
ization in humans remains to be fully clarified.
Studies on the time course of capillary growth in response
to training in humans suggest that the rate of capillary growth
is the greatest in the first weeks of training and then lev-
els off after approximately four weeks (192, 210). Although
capillarization clearly will increase with training beyond the
first weeks, it seems that the difference in capillarization
in untrained versus well-trained endurance athletes rarely
exceeds 2-fold to 2.5-fold (Fig. 8). In sedentary individuals,
values for capillary per fiber and capillary density generally
lie in the range of 1.5-2.5 and 300-400 caps/mm2 , respec-
tively, whereas in endurance trained athletes, capillary per
fiber ratio and the capillary density lie between 2-3.5 and
400-600 caps/mm2 , respectively (205, 340, 434, 469).
In accordance with the concept of symmorphosis (451),
endurance training potently increases capillarization in paral-
lel with improvements in the oxidative potential of the mus-
cle through enhanced mitochondrial capacity. Accordingly,
some of the regulatory pathways of mitochondrial biogene-
sis, including AMPK and peroxisome proliferator-activated
receptor gamma coactivator 1α activation, are also involved
in the regulation of capillary growth (12, 253, 254). In com-
paring mitochondrial volume density with capillary length
density in oxidative muscle and cardiac muscle of differ-
ent animal species, a clear relationship between these two
variables has been observed (Hoppeler and Kayar 1980). In
human skeletal muscle, the relationship between oxidative
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Cardiovascular Effects of Endurance Training
5 leading to exhaustion within 1 to 4 min (202). For exercise
20-40 years
41-60 years
61-80 years
4
Capillary-to-fibre ratio
3 sprint exercise, with energy supply originating mainly from
2
r 2 = 0,31
1
P < 0.001
0
10 20 30 40 50 60 70
VO2max (mL O2 min–1 kg–1)
Figure 9 Capillary-to-fiber ratio in relation to maximal oxygen uptake
in young, middle-aged, and older men of different training status. Capil-
lary number and muscle fibers were obtained by counting of immunohis-
tochemically stained transverse muscle sections cut from frozen muscle
(m.v. lateralis) samples. Maximal oxygen uptake was determined by
measurements of expired air during a graded cycle test to exhaustion.
Data adapted, with permission, from (150, 191, 201) and from Ander-
sen and Bangsbo (previously unpublished data) and Nyberg, Hellsten
and Mortensen (previously unpublished data).
capacity and capillary density may not be as clear but a rela-
tionship between aerobic power and capillarization can be
demonstrated (197, 469). Such a relationship is illustrated
in Figure 9 where the relationship between maximal oxygen
uptake and capillary per fiber ratio has been plotted for young,
middle-aged, and aged individuals of different fitness levels.
High-intensity intermittent training
When evaluating the effect of high-intensity intermittent train-
ing on capillary growth, it is important to consider that high
intensity intermittent training encompasses a large range of
intensities and durations, from intervals conducted close to
maximal aerobic power for periods of a few minutes, to very
brief intervals conducted at several hundred percent of max-
imal aerobic power. High intensity intermittent training per-
formed by inactive young males at intensities between 90%
and 170% of VO2max , has been found to induce a signifi-
cant increase in capillarization (211, 392). Moreover, in the
higher end of exercise intensities, Cocks et al. reported that
repeated all-out 30 s Wingate bouts lead to an increase in
capillarization (66). Accordingly, in rodents, high intensity
exercise has been shown to be similarly effective in induc-
ing capillarization (155, 222). Thus, based on existing data it
seems reasonable to conclude that high intensity training has a
similar effect on capillary growth as more moderate intensity
exercise in sedentary individuals.
The physiological relevance of an increase in capillariza-
tion in the muscle in response to high intensity training is
supported by the finding of a relationship between the level
of capillarization in muscle and performance at intensities
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Comprehensive Physiology
performed around peak aerobic power, the physiological rele-
vance of a high capillary density would lie in optimal oxygen
diffusion conditions at very high blood flows to accommo-
date the large aerobic energy demand. However, in interval
anaerobic energy production, an increased capillarization may
allow for faster oxygen dependent metabolic recovery pro-
cesses and serve to improve the removal of metabolic waste
products such as lactate. The latter physiological function is
supported by a study showing that selective chronic electrical
stimulation of glycolytic fast twitch fibers led to an increase
in capillarization (98).
80
Resistance training
As with exercise of very high intensity, resistance exercise
requires mainly energy from anaerobic energy sources in the
muscle thus capillarization may primarily be important for
removal of metabolic waste products. From existing data, it
seems likely that capillary growth in response to resistance
training mainly occurs when there is a parallel enlargement
in fiber area, ensuring that capillary density is maintained in
the muscle tissue (3). In accordance, the majority of studies
on the effect of resistance training on capillary growth show
no or minor effects on capillary density (27, 65, 424, 425).
Physiological signals that mediate exercise
training-induced capillary growth
A relevant question related to the efficacy of different forms of
exercise training in inducing capillary growth is which phys-
iological factors that provide signals for growth (Fig. 10).
This topic was initially addressed in skeletal muscle by Olga
Hudlicka, Stuart Egginton and co-workers at the University of
Birmingham in particular (99, 100, 465). Their work clearly
demonstrated that mechanical signals present during mus-
cle contraction, including shear stress and passive stretch,
are highly important stimulators of capillary growth. Shear
stress, which is elevated in the capillaries as the blood flow
to the muscle increases during dynamic exercise, is sensed
by mechanotransducers in the cell membrane. The mechan-
otransducers mediate the signal through the cytoskeleton of
the endothelial cells leading to increased expression of angio-
genic proteins (10, 459). Several compounds have been pro-
posed to be of importance for the transmission of shear stress,
including glycocalyx, PECAM-1, VEGFR2, and VE cadherin
(72,441). The other mechanical stimulus that promotes angio-
genesis, passive stretch of the tissue, occurs repeatedly when
the muscle contracts. The transduction of this mechanical
impact to the endothelial cells is poorly understood but may
involve integrins (429) and/or fibronectin (187).
Shear stress and passive stretch induce capillary growth
by two different processes. Shear stress induces capillary
growth by longitudinal splitting of the existing capillary; the
capillary endothelial cells grow inward into the lumen and
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Comprehensive Physiology Cardiovascular Effects of Endurance Training

Skeletal muscle
contraction

Shear stress Passive stretch Hypoxia

MMP-2 MMP-9 VEGF HIF-1α

eNOS VEGF

VEGF
Pro angiogenic compounds Tie-2 Ang-2

Anti angiogenic compounds Ang-1

Tie-2
TSP-1
Endostatin TIMP
PF-4
Soluble VEGF receptor

Figure 10 Dynamic muscle contraction provides mechanical signals of importance for capil-
lary growth: the associated increase in blood flow to the muscle leads to an increase in shear
stress on the capillary endothelium and the contractile process induces passive stretch of the tis-
sue. This mechanical impact promotes formation of angioregulatory factors, both pro- and antian-
giogenic in nature. To what extent capillary growth occurs in the muscle is determined by the
balance between the pro and the antiangiogenic factors. One of the most central proangiogenic
factors is vascular endothelial growth factor (VEGF) which interacts closely with nitric oxide formed
from endothelial nitric oxide synthase (eNOS), whereas thrombospondin-1 (TSP-1) may be a key
antiangiogenic factor. Apart from muscle contraction, hypoxia can induce angiogenesis in part
by an increase in the transcription factor hypoxia inducible factor-1α (HIF-1α) which promotes
VEGF expression. However, the actual impact of hypoxia on human muscle capillarization is
less certain. MMP: Matrix metalloproteinase, VEGF, vascular endothelial growth factor; eNOS:
endothelial nitric oxide synthase; TSP-1 thrombospondin.1; TIMP-1: tissue inhibitor of matrix met-
alloproteinase; ANG: angiopoietin; PF-4: platelet factor 4; Tie-2: angiopoietin receptor 2.

divide the lumen of the capillary into two parallel capillaries
(100, 357, 466). Passive stretch induces capillary growth pri-
marily by sprouting angiogenesis, where a new capillary is
budded off from an existing capillary (100, 465). Sprouting
angiogenesis requires somewhat more disintegration of the
basement membrane than the process of longitudinal splitting.
Capillary growth in response to muscle contraction probably
occurs by both processes.
In humans, evidence for a role of mechanical signals for
capillary growth has been provided by use of passive move-
ment of the lower leg. In this model the lower leg is passively
extended and flexed which induces stretch of the tissue and
increases flow and thereby shear stress, without an effect on
metabolism (178). An acute bout of passive movement stimu-
lates pro angiogenic factors (178) and weeks of repeated pas-
sive movement training, leads to a transient increase in prolif-
eration of endothelial associated cells and a small increase in
capillarization (194). These data support the notion from ani-
mal studies that mechanical factors are important in exercise-
induced angiogenesis in skeletal muscle.
In addition to mechanical factors, muscle contraction per
se and the associated increase in muscle metabolism may
also promote capillary growth. Extracellular fluid from con-
tracting skeletal muscle cells in culture contain the impor-
tant angiogenic growth factor VEGF and enhances endothe-
lial cell proliferation (213, 461). These observations suggest
that skeletal muscle cells release angiogenic compounds in
response to contraction. Provided that both shear stress and
metabolism are important factors for angiogenesis, it could
be assumed that exercise of higher intensities, inducing high
levels of blood flow and metabolism, would provide stronger
angiogenic signals than exercise of moderate intensity. It is,
however, probably not quite that straightforward as evidenced
by the finding that high intensity exercise does not appear
to result in more capillary growth than exercise of moderate
intensity (66,191,192,210). Moreover, a study was conducted
in which exercise training was switched from moderate inten-
sity to high-intensity interval training to examine whether
the added shear stress and metabolic stimulus would induce
capillarization beyond that observed with the first weeks of
moderate intensity exercise (192). The study revealed that no
further angiogenesis occurred after the first 4 weeks of mod-
erate training despite the added stimulus (192). One explana-
tion for these observations could be that there is a limitation

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Cardiovascular Effects of Endurance Training
to how much the capillary network structurally may be altered
within only a few weeks. Alternatively, there may not be any
functional benefit in enhancing the capillary network beyond
that achieved in the first training period, in relation to the
metabolic demands induced by the more intense training.
The final potential proangiogenic mechanism that has
been discussed with regard to exercise-induced angiogenesis
is hypoxia. In in vitro experiments, hypoxia has been shown to
promote endothelial cell activation, proliferation, and migra-
tion (279, 281). Moreover, hypoxia leads to an upregulation
of hypoxia inducible factor 1α which initiates transcription of
the central angiogenic factor VEGF (42). However, findings
from animals and humans do not show a clear angiogenic
effect of hypoxia. In fact, VEGF mRNA levels can even be
suppressed by hypoxia (43, 323, 324). A reasonable assump-
tion based on existing literature is that capillary density is
increased in chronic hypoxia but that this increase primarily
reflects a decrease in muscle fiber area and less so an increase
in capillary growth (196,273). It should, nevertheless be noted
that animal models of local ischemia in muscle clearly show
an effect on angiogenesis (180, 207) suggesting that more
severe conditions of low oxygen supply in the muscle may
provide a stimulus for capillary growth. It is questionable
whether hypoxia is present in muscle during normoxic exer-
cise. However, experimental models involving reduced blood
supply to the muscle in humans during exercise (154) and
animal models with training in hypoxia (324) have shown a
somewhat potentiating effect of training with reduced oxygen
supply on the angiogenic response to exercise.
To summarize, exercise-induced signals that promote cap-
illarization in skeletal muscle include both mechanical and
metabolically related signals and a training-induced increase
in capillarization is the result of an integration of such signals
present during exercise. When training sedentary individuals,
the intensity of the exercise training does not appear to play a
major role for the magnitude of capillary growth.
The effect of exercise training on
angiogenic compounds
The signals produced by mechanical and metabolic alterations
in the muscle during exercise mediate their effects via regula-
tory angiogenic compounds. These compounds which either
promote or inhibit angiogenesis are produced in the vascular
cells, the interstitial cells or in the muscle cells. The expres-
sion of numerous angiogenic compounds have been shown
to be affected by exercise in skeletal muscle, including the
proangiogenic compounds VEGF matrix metalloproteinases,
eNOS, and angiopoietin 2, and the antiangiogenic compounds
thrombospondin 1, endostatin, and tissue inhibitor of matrix
metalloproteinases (264, 322, 357, 375). The most central pro
angiogenic compound in skeletal muscle tissue known to date
is VEGF (263,325,423,448). VEGF is stored in large amounts
within the skeletal muscle fibers (159) but smaller amounts
are also present in other cell types such as endothelial cells
(124) and pericytes (193). In response to acute exercise there
20
November 9, 2015 13:21 8in×10.75in
Comprehensive Physiology
is a substantial transient increase in VEGF mRNA levels in
muscle tissue (43,126,153,355) and in VEGF protein levels in
the muscle interstitial fluid (127,188). The interstitial increase
in VEGF during exercise is believed to mainly originate from
secretion by skeletal muscle cells in response to mechanical
stimuli (213,221). The exercise-induced increase in VEGF in
the muscle interstitium is likely to be an important element
in capillary growth; however, regulation of capillary growth
clearly requires an orchestration of both proangiogenic and
anti angiogenic compounds in the muscle (95, 321). As an
example, data suggest that a lowering of antiangiogenic com-
pounds, such as TSP-1, actually may be essential for initiation
of angiogenesis (321, 322).
A general finding in response to exercise training is that
the acute exercise-induced increase in mRNA for proangio-
genic factors including VEGF is reduced after a training
period (191, 212, 267, 356). This reduced response seems to
be present once capillary growth has taken place and proba-
bly reflects that exercise-induced angiogenic signals, such as
those induced by shear stress, are reduced. Interestingly, the
anti angiogenic compound TSP-1 has been shown to increase
with training in parallel with a reduction in VEGF, further sup-
porting a retardation of capillary growth as adaptation occurs
(322). VEGF protein in skeletal muscle is, in rodents, consis-
tently found to be increased with chronic electrical stimula-
tion or exercise training (6, 11, 46). In humans, studies show
either unaltered (191,192) or increased (152,154) VEGF pro-
tein levels with training. The discrepancies between studies in
humans and animals may largely be related to that earlier time
points after onset of training are studied in rodents. A study
on the time course of expression of proangiogenic and antian-
giogenic compounds in rodents by Olenich and co-workers
suggests that VEGF levels are increased within a few days
of training and then reduced after 2 to 4 weeks of training
(320). This time course is consistent with findings in humans
showing an increase in muscle VEGF protein at 10 days of
training but similar VEGF protein levels after 4 weeks of
training (152). The return in VEGF toward baseline after 4
weeks of training also fits well with the finding that training
does not increase the exercise-induced secretion of VEGF to
the muscle interstitium in young subjects (127,191,192). This
transient effect of exercise training on the angiogenic poten-
tial underlines the open question of whether a similar rate of
capillary growth can be achieved after the first weeks of train-
ing. The obvious solution of a marked increase in training
intensity does not appear to provide the answer (192).
In relation to the above discussion, it is worth noting that
several exercise training studies have shown increased VEGF
protein levels in both muscle tissue and the muscle interstitium
in individuals with reduced cardiovascular health including
individuals with heart failure (151), and essential hyperten-
sion (160) but also in sedentary aged individuals (127, 134).
As stated above, training studies in humans and rodents
have examined a large number of proangiogenic and antian-
giogenic compounds in skeletal muscle in addition to VEGF,
although further studies are warranted to better understand
Volume 6, January 2016
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Comprehensive Physiology
their roles and interaction. The present article does not cover
data on the many other potentially important angiogenic com-
pounds, instead the reader is referred to excellent reviews that
specifically address this topic (95, 321).
To summarize, existing literature suggests that capillary
growth is regulated by a large number of pro- and antian-
giogenic compounds that mainly are transiently altered with
acute exercise and exercise training. In accordance, although
endurance training is a potent stimulator of capillary growth,
the angiogenic potential, as determined by the expression of
proangigenic versus antiangiogenic compounds, is not neces-
sarily greater in a trained than an untrained young healthy indi-
vidual whereas the potential may be improved with training in
individuals with an originally reduced angiogenic potential.
The role of muscle characteristics in angiogenesis
The majority of data on training-induced capillary growth
in healthy individuals stems from determinations in the
muscle vastus lateralis. The vastus lateralis muscle has a
mixture of Type I, Type IIa, and Type IIx fiber types and
most individuals have a similar number of Type I and Type II
muscle fibers although outliers exist (259). The mix of fiber
types means that most capillaries are shared between Type I,
Type IIa, and to some extent Type IIx fibers, thus the effect
of a training regimen on capillary growth in relation to fiber
type is not so easily assessed in humans but can be detected
as illustrated in Figure 11. Cross sectional data indicate that
endurance athletes have a higher (205) or similar (80) number
of capillaries around Type I versus around Type II fibers
and after high intensity training an unaltered distribution of
capillaries around Type I and Type II fibers has been observed
(210). In contrast to human muscle, rodent locomotor muscle
4.0
3.5
3.0
Capillary-to-fibre ratio
2.5
2.0
1.5
1.0
0.5
20 30 40 50 60
MHC I (%)
Figure 11 Capillary-to-fiber ratio in relation to Myosin Heavy chain
1 (MHC I) positive muscle fibers in subjects of different fitness level
(25-65 mL O2 min−1 kg−1 ) and age (20-71 years). Capillary number
and muscle fibers were obtained by counting of immunohistochemically
stained transverse muscle sections cut from frozen muscle (m.v. lateralis)
samples. Data adapted, with permission, from (150) and Nyberg, Hell-
sten and Mortensen (previously unpublished data).
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Cardiovascular Effects of Endurance Training
shows a more uniform distribution of fiber types where the
different muscle groups consist mainly of one fiber type.
Studies on capillary growth with training in rodents show
that capillary growth is most marked in glycolytic muscle
(17, 264).
Adaptations in Inactive Skeletal Muscle
There is evidence for that endurance training also affects
the vasculature in nonactive muscle during exercise with the
most distinct effect observed in individuals or animal mod-
els with impaired endothelial function (326). A number of
studies have shown that FMD is improved in the forearm con-
duit artery after a period of cycling training with the legs
(33, 144, 262, 327). One likely mechanism underlying the
improvement in the nonactive limb is an increase in shear
stress, as demonstrated in a study by Tinken et al. in which
the blood flow to one of the forearms was occluded during leg
exercise training and improvements were observed only in the
non-occluded arm (432). The increase in shear stress in the
non-active forearm may have been due to an increase in cuta-
neous blood flow associated with the increase in temperature
during exercise (308).
Endothelial function of resistance arteries may also be
improved in nonactive skeletal muscle with a period of exer-
cise training. Improved endothelial function in nonactive mus-
cle has been demonstrated in animal models by assessment
of the responsiveness to an endothelial-dependent vasodilator
such as ACh (241, 242, 460). The mechanism underlying the
adaptations in resistance arteries of nonactive limbs remains
uncertain but circulating factors and shear stress are likely
contributors to the effect (326).
With regard to the possible effect of exercise training
and shear stress on changes in microvascular growth in inac-
tive muscle, an observation was made in a study on humans
in which the effect of passive movement training on the
angiogenic response in skeletal muscle was examined. The
study showed that passive movement, which induces an NO-
dependent increase in blood flow, and thus shear stress, with-
out a metabolic demand (178,194,287), lead to an angiogenic
response, as evidenced by upregulation of angiogenic fac-
tors, a transient increase in proliferating cells associated with
muscle capillaries and a small increment in capillarization
(194). In addition, in the nontrained leg, a small increase in
r 2 = 0.493
P < 0.001 capillarization and an increase in the mRNA level of angio-
genic factors were detected. These observations agree with
the important role of shear stress for vascular adaptations and
70 80 90 100 indicate that training can induce vascular adaptations also in
inactive muscle.
The effect of exercise training on adaptations in
other tissues
The effects of exercise training include also alterations in
the vascular control in many tissues other than cardiac and
21
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Cardiovascular Effects of Endurance Training
skeletal muscle. The adaptations include primarily changes
in endothelial phenotype and function but may also entail
an increased microcirculatory network. One example is the
cutaneous circulation, which during exercise, has a primary
function in the dissipation of heat. The cutaneous circulation is
under the control of the sympathetic nervous system, both via
cholinergic vasodilatation, involving corelease of ACh with a
second neurotransmitter, and via adrenergic vasoconstriction
(226, 227). During acute exercise, the cutaneous circulation
is increased at the time when core temperature rises. Exer-
cise training has been shown to lead to an increase in cuta-
neous blood flow at a lower core temperature (358) and to an
increased magnitude of skin blood flow for a given core tem-
perature (420). In accordance, cross sectional comparisons of
untrained and well-trained individuals show that skin blood
flow during exercise in the heat is higher in well trained than
in the untrained individuals (185). These systemic adapta-
tions may primarily be associated with the training-induced
increase in plasma volume, as plasma volume is a determining
factor for cutaneous perfusion (138, 204). The local respon-
siveness of the skin, for example, with local heating (360) or
in response to ACh (238, 450), is also improved by exercise
training, an effect that may be due to a greater contribution
by NO and prostaglandins (92, 360), at least in part, induced
by repetitive increases in shear stress (308).
Other organs, in which exercise training has been
documented to induce changes in blood flow and vascular
function, include the brain (4,37), and the splanchic and renal
circulation (60, 84, 243, 306). In the brain, the most marked
effect of exercise training probably lies in protection against
cerebrovascular events and in improvement in brain function,
where the latter effect is observed primarily in individuals with
reduced cardiovascular health (235, 252, 452). There may be
multiple explanations for this phenomenon but an improved
vascular function and perfusion of the brain are likely
contributing factors. Ainsle et al. showed in a cross-sectional
study that middle cerebral arterial blood flow at rest is higher
in individuals that conduct regular physical activity (4). Simi-
larly, Barnes and co-workers reported that the cerebrovascular
reactivity to hypercapnia was related to the aerobic fitness
level in aged men (22). The study also reported that inhibition
of prostanoid synthesis reduced the cerebrovascular reactivity
to a greater extent in individuals with high aerobic power,
suggesting that one of the underlying mechanisms was related
to prostanoids (22). Moreover, the beneficial effect of training
may in part be related to NO availability as indicated by the
observation that the increase in resting cerebral perfusion
after exercise training was absent in mice in which NO
formation had been experimentally abolished (129). There
is also evidence for that carotid artery structure and function
is improved and that atherosclerotic plaque is reduced with
exercise training (218, 342). Although the mechanisms of
improved cerebral vascular function remain unclear, as in
other tissues, shear stress may be an important contributing
factor.
22
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Comprehensive Physiology
In the splanchic and renal region, the primary effect of
exercise training is a higher blood flow during exercise at
the same absolute submaximal work rate (14, 63, 339, 369).
The mechanisms underlying the training-induced increase in
splanchic blood flow have been proposed to be a reduced
sympathetic influence (275, 280) and improved vasodilator
capacity (60, 84, 416).
Combined, these examples emphasize the influence of
exercise training on vascular control and function in many of
the organs of the body to optimize aspects of importance for
performance and with a close coupling to health.
Conclusion
Effective endurance training can result in substantial adap-
ations in the cardiovascular system ranging from improved
cardiac and arterial dimensions and function and an increased
number of microcirculatory vessels in skeletal and cardiac
muscle (Fig. 12). Such adaptations are important for an
improvement in aerobic power and performance but can
also significantly improve cardiovascular health in sedentary
individuals. A vast number of studies have characterized the
functional adaptations that occur with endurance training
in healthy young and aged individuals and in individuals
with life style related disease. However, less is known
regarding the cellular and molecular mechanisms underlying
the cardiovascular changes with regular physical activity. For
example, although our understanding regarding the control
of exercise hyperemia has markedly advanced over the last
decades, we still do not have a complete picture of which
vasoregulatory mechanisms and compounds that are the
most central or how physical activity affects these systems.
An experimental limitation in this area is the complexity of
the regulation where redundancy between compounds and
mechanisms make conclusive designs difficult. In the area of
capillary growth in skeletal muscle substantial advancements
have been made, in particular regarding the influence of
mechanical factors such as shear stress and passive stretch
for the promotion of capillary growth. However, similarly
to the regulation of exercise hyperemia, angiogenesis is a
highly complex process involving an orchestration of a large
number of pro- and antiangiogenic compounds with different
time courses due to their specific involvement in the several
steps of the development of a new capillary. Thus, although
our knowledge regarding these processes and compounds
and how they are affected by physical activity has improved,
many aspects remain to be elucidated. Therefore, important
areas that future studies should focus on are the cellular and
molecular mechanisms underlying the regulation of vascular
tone and micro- as well as macrovascular growth in skeletal
muscle. Furthermore, effort should be made to improve our
understanding of the signals and molecular pathways under-
lying the training adaptations in cardiac tissue and cardiac
microvessels.
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Comprehensive Physiology Cardiovascular Effects of Endurance Training

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The research of the authors has been funded by The Dan-
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