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Peptides 32 (2011) 21412150

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Peptides
journal homepage: www.elsevier.com/locate/peptides

Review

A new look at the reninangiotensin systemFocusing on the vascular system


Aurelie Nguyen Dinh Cat, Rhian M. Touyz
Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Rd, Ottawa, ON KIH 8M5, Canada

a r t i c l e

i n f o

Article history:
Received 23 August 2011
Accepted 7 September 2011
Available online 16 September 2011
Keywords:
Tissue RAS
Renin
Circulating RAS
Vascular tone
Ang-(1-7)
Vascular cells

a b s t r a c t
The reninangiotensin system (RAS), critically involved in the control of blood pressure and volume
homeostasis, is a dual system comprising a circulating component and a local tissue component. The
rate limiting enzyme is renin, which in the circulating RAS derives from the kidney to generate Ang II,
which in turn regulates cardiovascular function by binding to AT1 and AT2 receptors on cardiac, renal
and vascular cells. The tissue RAS can operate independently of the circulating RAS and may be activated
even when the circulating RAS is suppressed or normal. A functional tissue RAS has been identied in
brain, kidney, heart, adipose tissue, hematopoietic tissue, gastrointestinal tract, liver, endocrine system
and blood vessels. Whereas angiotensinsinogen, angiotensin converting enzyme (ACE), Ang I and Ang II
are synthesized within these tissues, there is still controversy as to whether renin is produced locally
or whether it is taken up from the circulation, possibly by the (pro)renin receptor. This is particularly
true in the vascular wall, where expression of renin is very low. The exact function of the vascular RAS
remains elusive, but may contribute to ne-tuning of vascular tone and arterial structure and may amplify
vascular effects of the circulating RAS, particularly in pathological conditions, such as in hypertension,
atherosclerosis and diabetes. New concepts relating to the vascular RAS have recently been elucidated
including: (1) the presence of functionally active Ang-(1-7)-Mas axis in the vascular system, (2) the
importance of the RAS in perivascular adipose tissue and cross talk with vessels, and (3) the contribution
to vascular RAS of Ang II derived from immune and inammatory cells within the vascular wall. The
present review highlights recent progress in the RAS eld, focusing on the tissue system and particularly
on the vascular RAS.
2011 Elsevier Inc. All rights reserved.

Contents
1.
2.
3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The classical RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Beyond the classical RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Renin/prorenin receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
ACE2, Ang-(1-7), Ang III, Ang IV and other Ang-derived peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Intracellular RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.
Tissue-based RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.
The vascular RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.
Ang-derived peptides in the vascular wall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.
The RAS in perivascular adventitial tissue (PVAT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.
Functional evidence of vascular tissue RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.
The vascular RAS and hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.
The (patho)physiological signicance of the vascular RAS further considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

This is part of a series of reviews on local reninangiotensin systems edited by


Walmor C. De Mello.
Corresponding author. Tel.: +1 613 562 5800x8241; fax: +1 613 562 5487.
E-mail address: rtouyz@uottawa.ca (R.M. Touyz).
0196-9781/$ see front matter 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.peptides.2011.09.010

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1. Introduction
The reninangiotensin system (RAS) is critically involved in the
physiological regulation of blood pressure and volume homeostasis
and in the pathogenesis of hypertension and other cardiovascular
diseases [43,137]. Pharmacological inhibition of the RAS is a major
therapeutic strategy currently used to manage hypertension and to
reduce the risks of cardiovascular events [6]. Since its discovery in
the 1890s the RAS was identied as an endocrine system whereby
circulating kidney-derived renin regulates cardiovascular function
through Ang II binding to its receptors on target tissues [149]. Until
recently this system was accepted as the conventional RAS. However it is now clear that the kidney is not the only source of renin
production and that angiotensin (Ang) peptides may be formed in
tissues and organs that have a blood pressure-independent function.
Genes coding for enzymes and peptides of the RAS are expressed
in many tissues beyond the kidney, including the brain, adrenal
gland, pituitary gland, reproductive tissues, gastrointestinal tract,
hematopoietic tissue, heart and vessels, suggesting the presence
of a functionally active local or tissue RAS [10,24,142]. Functions
of the local RAS remain elusive, but are probably tissue-specic.
The exact role of tissue RAS in human (patho)physiology is still
unclear. The present review provides an update of the classical RAS
and highlights some new concepts, focusing on the tissue RAS and
specically the vascular RAS.

2. The classical RAS


Activation of the classical RAS originates with the synthesis
of renin, a glycoprotein, by the juxtaglomerular (JG) cells of the
renal afferent arteriole [57]. In JG cells, preprorenin is processed
to prorenin and then to active renin, which is secreted into the
circulation [95]. Renal renin release is stimulated by low volume
states, high salt content in the distal tubules, renal sympathetic
nerve activity and reduced renal perfusion [70,150]. In the blood,
renin, an aspartyl protease, cleaves liver-derived angiotensinogen
to form the decapeptide angiotensin I (Ang I) [53]. Angiotensin converting enzyme (ACE) hydrolyzes inactive Ang I into the biologically
active octapeptide Ang II. ACE is found primarily in endothelial cells
(especially pulmonary endothelium) [63]. In addition to cleaving
Ang I, ACE metabolizes bradykinin (BK), a vasodilator, to inactive
BK-(1-7) [20]. Hence ACE has a dual role in the vasculature in that it
promotes the production of Ang II, a potent vasoconstrictor while
degrading BK, a vasodilator.
Vascular, cardiac, renal and adrenal effects of Ang II are mediated via two G protein-coupled receptors (GPCR), the Ang type
1 (AT1 ) receptor and the Ang type 2 (AT2 ) receptor that act, in
general, in opposite directions. The AT1 receptor interacts with
multiple heterotrimeric G-proteins and produces second messengers, such as inositol trisphosphate (IP3 ), diacylglycerol (DAG)
and ROS [64]. Ang II/AT1 receptor coupling activates receptor and
non-receptor tyrosine kinases, serine/threonine kinases, MAPKs,
p70S6K, Akt/PKB and PKC [64,91] and couples negatively to adenyl
cyclase [151]. Most of the (patho)physiological effects of Ang II
are mediated through AT1 receptors including vasoconstriction,
aldosterone secretion, renal tubular Na+ reabsorption, thirst, activation of the sympathetic nervous system, cardiac ionotropic and
chronotropic actions and cardiovascular inammation, hypertrophy and brosis [97,127,155].
The AT2 receptor shares partial amino acid homology (34%) to
AT1 receptors and is the predominant Ang II receptor in the fetus
[55]. It is expressed at low levels in the adult vasculature, JG cells,
glomeruli and tubules and it elicits effects to counteract those of
the AT1 receptor [66]. The AT2 receptor mediates actions through

protein tyrosine phosphatase activation, NO generation and signaling through sphingolipids to stimulate vasodilation, natriuresis,
anti-inammatory and anti-brotic actions and inhibition of cell
growth [77,128]. Increased AT2 R expression occurs in pathological
conditions including: hypertension, myocardial infarction, cardiac
failure, renal failure, cerebral ischemia and diabetes, possibly as a
stress response where fetal genes are re-expressed [1,129,134].
GPCRs interact not only with G proteins but also with accessory
proteins, termed GPCR interacting proteins (GIP). GIP specically
associated with AT1 R, called AT1 R-associated protein (ATRAP), acts
as a negative regulator of AT1 R [5] and is expressed in aorta, heart,
lung and kidney. Overexpression leads to decreased cell proliferation. Another GIP, ARAP1 (AT1 R-associated protein 1), is involved
in recycling of the AT1 receptor [92,146]. GPCR interacting proteins
associated with AT2 R, include AT2 R-interacting protein (ATIP) (also
known as mitochondrial tumor suppressor gene 1 (MTUS1) and
AT2 R binding protein of 50 kDa (ATBP50)) is involved in transinactivation of receptor tyrosine kinases and growth inhibition [105].
The biology and regulation of Ang receptors has been extensively
reviewed [90,101].
3. Beyond the classical RAS
Until recently, the RAS was considered a linear process (Fig. 1)
and Ang II was accepted as the major effector peptide [143]. However the conventional view of the RAS has undergone signicant
change at four main levels: (1) identication of renin/prorenin
receptor, (2) recognition of functionally active Ang II-derived peptides, (3) intracellular RAS and (4) existence of a tissue RAS. The
present review highlights some of these new paradigms focusing
on the tissue system, specically the vascular RAS.
3.1. Renin/prorenin receptor
Renin was considered to be a protease enzyme responsible
for production of Ang I without any direct biological actions.
However it has now been shown that prorenin and renin
bind to specic (pro)renin receptors ((P)RR) [98,99], which activate signaling molecules, including promyelocytic zinc ngers
(PLZF), protein-phosphatidylinositol-3-kinase (PI3K) and mitogenactivated protein (MAP) kinases (ERK1/2 and p38MAP kinase),
promoting cell growth and brosis, independently of Ang II,
in cardiomyocytes, mesangial cells, podocytes, distal tubular
cells, vascular endothelial cells and VSMCs [27,119]. The exact
(patho)physiological signicance of the (P)RR remains unclear
although it may act as an amplier of tissue RAS.
The (P)RR is a multifunctional receptor that mediates effects
beyond the RAS [65]. A truncated form of the receptor (M8.9), may
be an accessory protein of vacuolar H+ -ATPase (V-ATPase) involved
in non-RAS-related functions [86]. The (P)RR/ATP6AP2 is essential for vacuolar H+ -ATPase assembly in cardiomyocytes [3,71].
V-ATPase plays a role in physiological and biochemical processes by
regulating intracellular pH, an effect that is enhanced by (pro)renin
binding to (P)RR [23]. The (P)RR also acts as an adaptor protein
between V-ATPase and Wnt receptors and signals through Wnt in
a (pro)renin-independent manner [23]. Wnt signaling is involved
in cell proliferation, polarity, and fate determination during embryonic development and tissue homeostasis and has been implicated
in various pathologies including cancer.
3.2. ACE2, Ang-(1-7), Ang III, Ang IV and other Ang-derived
peptides
A homologue of ACE, ACE2 catalyzes Ang I and Ang II to generate the Ang peptides Ang-(1-9) and Ang-(1-7), which mediate,

A. Nguyen Dinh Cat, R.M. Touyz / Peptides 32 (2011) 21412150

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Angiotensinogen
Renin
Bradykinin

Angiotensin I
ACE
ACE2

Inactive
metabolites

Vasodilati
dil tion

Angiotensin II

AT1R

Angiotensin-(1-7)

Mas

AT2R

Vasoconstriction
Fibrosis
Hypertrophy
Inflammation

Vasodilation
Anti-fibrotic
Anti-growth
Anti-inflammatory

Fig. 1. The classical reninangiotensin system. Kidney-derived renin is secreted into the circulation where it cleaves liver-derived angiotensinogen to angiotensin I, which
is hydrolyzed to angiotensin II (Ang II) by angiotensin converting enzyme (ACE). ACE metabolizes bradykinin to inactive metabolites. A homologue of ACE, ACE2, catalyzes
Ang II to Ang-(1-7). Ang II binds to Ang II type 1 receptors (AT1 R) and Ang II type 2 receptors (AT2 R) on vascular cells, mediating vascular effects. Ang-(1-7) binds to receptor
Mas and induces effects similar to those mediated by AT2 R.

in general, opposite effects to those of Ang II [28,42]. Ang-(17) is metabolized by ACE to Ang-(1-5). Ang-(1-7) is present in
the circulation and in tissues (brain, heart, kidneys, vessels, liver,
reproductive organs) [52,125], and binds to its G protein-coupled
receptor Mas [126].
Other small peptides derived from Ang II include Ang III and Ang
IV. Ang III, formed from Ang II by aminopeptidase A, is a biologically active peptide with actions similar to those of Ang II [8]. Ang
III infusion in experimental models and in humans increases BP,
promotes vasoconstriction and stimulates aldosterone production
[107]. In vitro, it stimulates growth, production of proinammatory
mediators and deposition of extracellular matrix proteins [158].
Ang III binds to AT1 R, as well as to AT2 R. Ang IV is generated from
Ang III by aminopeptidase N and directly from Ang II by the enzyme
d-aminopeptidase. Ang IV increases renal blood ow, it induces
vasodilation and improves cardiac function [165]. Ang IV also exerts
a wide range of neural effects including the ability to enhance
learning and memory recall, anticonvulsant and anti-epileptogenic
properties and protection against cerebral ischemia. Some of these
actions are mediated via the AT1 R, but others are due to binding
to a specic binding site, AT4 R, identied as the transmembrane
enzyme insulin-regulated aminopeptidase (IRAP) [80]. Exact mechanism(s) of action whereby Ang IV induces effects via IRAP are
unclear and the biological signicance of Ang IV/IRAP remains to
be elucidated.
Other Ang peptides include Ang-(3-7), important in the brain
and kidney [44], Ang-(1-9), which enhances bradykinin actions, NO
production, and platelet regulation [100] and Ang-(1-12), implicated in cardiac function [25].

3.3. Intracellular RAS


The intracellular RAS is characterized by the presence of RAS
components within the cell and the ability of cells to synthesize Ang II, which elicits biological effects through intracellular
sites [75]. Although the intracellular presence and/or synthesis
of Ang II and its receptors have been demonstrated in many cell
types [30] there is less evidence that the other RAS components,
renin, angiotensinogen and ACE are located within cells. However
the cytosolic presence of differentially glycosylated isoforms of
angiotensinogen, alternatively spliced forms of renin, intracellular and secreted forms of ACE and alternative Ang II-generating
enzymes (cathepsins and chymase) and intracellular (P)RR, suggest a putative cytosolic RAS [74,121]. The demonstration of nuclear
Ang and Ang-(1-7) receptors further supports a functional cytosolic
RAS [59,60]. The intracellular RAS, which is probably an extension
or alternative form of tissue RAS, has been identied in the kidney, brain and heart. Overexpression of intracellular Ang II, using a
novel uorescent fusion protein of Ang II, correlates with elevated
BP and kidney pathology [81]. However the (patho)physiological
role of the endogenous system remains unclear.
3.4. Tissue-based RAS
The circulating RAS is only one entity of the overall RAS and
tissue RASs can function independently of the circulating system.
The tissue system is characterized by the presence of all RAS components, including renin, angiotensinogen, ACE, Ang I, Ang II, and
Ang II receptors and is found in the heart, vessels, kidney, adrenal

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A. Nguyen Dinh Cat, R.M. Touyz / Peptides 32 (2011) 21412150

Heart

Vessels
Adipose
tissue

Kidney
Brain

Tissue
RAS

Immune cells

Gastrointestinal
tract

Hematopoietic
tissue

Endocrine
Tissue
Reproductive
tissue

Liver

Pancreas,
Adrenal, pituitary

Fig. 2. Tissue reninangiotensin systems. Components of the reninangiotensin system are expressed in multiple organs and tissues, some of which are directly involved
in cardiovascular regulation (e.g. heart, vessels and kidneys) and others which are unrelated to cardiovascular control (e.g. Reproductive tissue, pancreas, gastrointestinal
system).

gland, pancreas, CNS, reproductive system, lymphatic and adipose


tissue [11,110,138,147] (Fig. 2). Elements of the RAS have also
been identied in the eye, which may be important physiologically
in maintaining ocular pressure [41] and pathologically in vasculopathies associated with retinopathy of hypertension and diabetes
[41,164]. Although it is fairly well established that tissue Ang II is
produced from locally derived Ang I, there is still uncertainty as
to whether tissue renin is synthesized locally or whether tissues
take up kidney-generated renin from the circulation. Renin may be
secreted locally in the kidney, adrenal glands and brain, but in the
heart and vessels, it seems to be primarily kidney-derived.
The local RAS acts in an autocrine/intracrine, paracrine and
endocrine fashion. Elevated tissue levels of RAS components occur
in cardiovascular diseases independently of BP elevation, such as,
atherosclerosis, myocardial infarction, cardiac failure, diabetes and
kidney disease [114]. The best characterized tissue RASs include
those in the brain, kidney and heart, and have recently been
reviewed [9,31,165,166].

support the presence of a functional vascular renin system in in


vitro conditions, aliskiren (direct renin inhibitor) increases the half
life of renin and prorenin in rat vascular smooth muscle cells overexpressing human (P)RR [13].
Conrming the presence of vascular renin in physiological conditions has been more challenging than in in vitro studies. Prorenin
and renin have been demonstrated in microvessels of the developing kidney [19] and in renal arteries from adult rats treated
with ACE inhibitors [112]. However renin expression in the vessel wall is hardly detectable and there is still a strong notion
that the vasculature itself is likely not a major source of local
renin. Vascular (P)RR probably plays a role in the uptake of the
enzyme from the circulation into the vessel wall. Moreover, the
contribution of vascular/tissue renin to circulating levels is unclear
because binephrectomized animals and anephric patients have
undetectable circulating renin [112].

5. Ang-derived peptides in the vascular wall


4. The vascular RAS
All the elements of the RAS are present in the vasculature,
indicating that the vascular system may act independently from
the systemic RAS to generate Ang II (Fig. 3). Expression of renin,
angiotensinogen, ACE, Ang I and Ang II has been demonstrated at
the mRNA and/or protein levels in veins (saphenous and umbilical), large conduit arteries (aorta) and small resistance arteries,
primarily within the endothelium [4,104,109,145]. Because regulation of tissue RAS occurs locally, the concentration of Ang II and
its active metabolites may vary between tissues and may be higher
in microvessels than that in the plasma [26].
Whereas there is general agreement that Ang II is synthesized
within the vessel wall, there is still controversy as to whether
renin is synthesized locally or whether it is taken up as kidneyderived renin from the circulation. The concept that vessels are
capable of synthesizing and releasing renin was rst reported in
the 1970s where it was shown that renin is released from isolated
rat hindquarters and splanchnic vessels and that renin activity is
present in vascular extracts [48,54]. Cultured canine and rat aortic smooth muscle cells and human arterial cells synthesize and
secrete renin [76,115,144]. Renin activity is greater in aortic cells
from SHRsp compared with WKY and has been implicated in augmented Ang II vascular effects in hypertension [148]. To further

In addition to classical RAS components being identied in vessels, new members of the RAS have been detected, including ACE2,
Ang-(1-7) and Mas. Vascular ACE2 is functionally active and generates Ang-(1-7) from Ang II. Ang-(1-7) is found in the endothelium
and vascular wall [32,136,161] and immunohistochemical staining shows abundant presence in aortic perivascular adventitial
tissue (PVAT) [78,79]. Ang-(1-7), by binding to receptor Mas on
endothelial cells, opposes Ang II actions by mediating vasodilation,
growth-inhibition, anti-inammatory responses, antiarrhythmogenic and antithrombotic effects [123,124] through NOS-derived
NO production, activation of protein tyrosine phosphatases,
reduced MAPK activation and inhibition of NADPH oxidase-derived
generation of reactive oxygen species (ROS) [123,124]. Overexpression of ACE2 in the vascular wall of SHR is associated with improved
endothelial function and attenuated development of hypertension
[117]. Ang-(1-7)-Mas can hetero-oligomerize with AT1 R, thereby
inhibiting Ang II actions. The ACE2-Ang-(1-7)-Mas axis is now considered as a counter-regulatory system to the ACE-Ang II-AT1 R axis
in the vasculature [113], although some evidence indicates that
Ang-(1-7) may also promote brosis and inammation in certain
conditions [40,156].
ProAng-12, a recently characterized metabolite of angiotensinogen, is the newest functional peptide of the RAS to be identied.
It might serve as an alternate substrate for local Ang production

A. Nguyen Dinh Cat, R.M. Touyz / Peptides 32 (2011) 21412150

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Fig. 3. Vascular reninangiotensin system. All components of the RAS are present in vascular cells. The expression of vascular renin is very low and probably derives primarily
from circulating renin, which is taken up from the circulation through (pro)renin receptors. Membrane-associated angiotensin converting enzyme (ACE) hydrolyzes Ang I
to Ang II, both in the extracellular and in the intracellular milieu. Vascular ACE2 catalyzes Ang II to Ang-(1-7). Ang II and Ang-(1-7) bind to their respective receptors. Ang II
may also be generated from renin-independent processes involving ProAng-12.

by circumventing the classical renin-dependent conversion of


angiotensinogen to Ang I [16]. ProAng-12 is produced in rat aorta
and may contribute to Ang I production independently of renin
in the vascular wall [111]. Functionally proAng-12 induces vasoconstriction through ACE1- and chymase-dependent mechanisms
[16]. However the (patho)physiological signicance of vascular
proAng-12 requires further clarication.

6. The RAS in perivascular adventitial tissue (PVAT)


Increasing evidence shows a paracrine role of PVAT in the
regulation of vascular function mediated, in part, through
adipocyte-derived vasoactive agents and pro-inammatory
cytokines [38,45,56,83]. Of the many adipocyte-generated factors
is Ang II [47,56]. Other members of the RAS have been identied in adipose tissue and PVAT, including angiotensinogen,
ACE, (pro)renin receptor, Ang II receptors and mineralocorticoid

receptors [2,14,17,18,21,22,37,58,131] (Fig. 4). A comprehensive


study examining the RAS in perivascular adipose tissue of the aorta
and mesenteric arteries from WKY rats demonstrated the presence
of angiotensinogen, ACE, ACE2, Ang I and Ang II [47]. In addition,
(P)RR, chymase, AT1a and AT2 receptors were expressed [47].
However renin was undetectable, both at the mRNA and protein
levels, and the AT1b receptor was barely detectable in PVAT. Levels
of expression of angiotensinogen, ACE and ACE2 were similar in
PVAT from aorta and mesenteric arteries. Expression of (P)RR was
ve times higher and that of chymase and AT1a and AT2 receptors
was signicantly lower in aortic PVAT compared with mesenteric
artery PVAT. Whereas levels of adipose Ang I were similar between
vascular beds, Ang II levels were higher in mesenteric artery
PVAT than aortic PVAT [104]. The functional signicance of these
differences is unclear, but may contribute to differential responses
to adipocyte-derived factors emanating from brown adipose
tissue versus white adipose tissue. Periaortic adipose tissue has
been identied as brown adipose tissue expressing uncoupling

Fig. 4. The adipocyte reninangiotensin system in perivascular adventitial tissue (PVAT) inuences vascular function and contributes to the vascular reninangiotensin
system. Adipocyte-derived Ang II, Ang-(1-7) and aldosterone inuence vascular function through specic vascular smooth muscle cell (VSMC) receptors. Production of
adipocytokines in response to locally generated Ang II may also impact vascular function. Adipocyte-derived renin may be taken up by vascular cells to stimulate production
of Ang II within vascular cells. AT1 R, Ang II type 1 receptor; MR, mineralocorticoid receptor.

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protein-1 (UCP-1), whereas mesenteric artery adipose tissue is


considered to be white adipose tissue [47].
Within PVAT, ACE2 activity promotes production of Ang-(1-7)
from Ang II, both in arteries and in veins [79,84]. Ang-(1-7) released
by PVAT induces production of endothelial NO, which acts as a
hyperpolarizing factor through K(Ca) channels to induce vasorelaxation [50]. These PVAT-derived Ang-(1-7) effects are altered
in vessels from SHR contributing to endothelial dysfunction and
impaired vasodilation in hypertension [50].
We recently demonstrated that mouse and human visceral adipose tissue and PVAT produce aldosterone in an Ang II-dependent
manner [96], processes that inuence vascular inammatory
responses. PVAT-derived components of the RAS provide an important mechanism for cross talk between adipocytes and vascular
cells [96,140]. Adipocyte RAS components may contribute to
increase the local synthesis of Ang II [85], which in turn may
exert autocrine/paracrine effects on adipocytes and on adjacent
vascular tissue [15,39,46,49,51,56,68,88,89,102]. These phenomena may be particularly important in vascular dysfunction and
insulin sensitivity associated with obesity, metabolic syndrome and
hyperaldosteronism [38,67,83].

7. Functional evidence of vascular tissue RAS


Vascular actions of circulating-derived and tissue-generated
Ang II are mediated via AT1 and AT2 receptors, located on endothelial cells, vascular smooth muscle cells and adventitial broblasts
[64,91]. Ang II mediates effects via complex signaling pathways
that are stimulated following to its cell-surface receptors [82]. Both
receptors regulate VSMC function, although they differ in their
actions. Whereas the AT1 R is associated with growth, inammation and vasoconstriction, the AT2 R is associated with apoptosis
and vasodilation [82,141]. In pathological conditions, AT2 R may
also stimulate hypertrophy and inammation [160]. Vascular RAS
may play an important role in the ne-tuning of vascular tone.
The concept of the vascular RAS and the autocrine/paracrine
role of vascular Ang II was suggested in the 1980s [33]. Vascular
cell Ang II stimulates synthesis of prostaglandins, endothelin-1 and
aldosterone in the endothelium and vessel wall, which in turn inuences vascular function [33,97,127,155]. Endothelial-derived Ang II
activates vascular smooth muscle Ang receptors and controls vascular tone. Vascular Ang II may also inuence catecholamine release
and reuptake by noradrenergic nerve endings [33]. The intrinsic
autocrine/paracrine RAS may contribute little to the circulating
RAS.
Identifying the source (systemic versus vascular) of Ang II
responsible for vascular regulation in physiological conditions is
challenging. However, there is evidence that intravascular Ang
II can directly inuence vascular function. In pig pial arteries,
intravascular Ang II induces AT1 receptor-mediated, endotheliumdependent vasodilation that is blocked by COX and NOS inhibition,
whereas local Ang II induces vasoconstriction or vasodilation [72].
In hypertension, the concentration of Ang II within microvessels is
higher than in plasma, and may contribute to increased vascular
tone. Some studies have shown an increase in the concentration
of tissue renin in vessels from SHR versus normotensive controls [157] and may reect an overactive local vascular RAS in
hypertension. Similar ndings have been reported in models of
atherosclerosis, suggesting a role for vascular RAS activation in
the pro-inammatory, pro-thrombotic and atherogenic processes
associated with atherosclerosis [73,139].
Recent studies have demonstrated that macrophages and various T-cell lymphocyte subtypes within the vascular wall play a
key role in the regulation of blood pressure and target organ damage [12,61]. Mice decient in T-lymphocytes [93,159] and mice

decient in monocytes/macrophages [29], fail to develop hypertension, endothelial dysfunction, vascular remodeling or vascular
inammation following Ang II infusion. Since macrophages and T
lymphocytes express components of the RAS, it is possible that
immune/inammatory cells may contribute to local Ang II levels
in the vessel wall. Expression (mainly mRNA) of angiotensinogen,
ACE and AT1 receptors and Ang II protein has been demonstrated
in macrophages, mast cells and lymphocytes [62,94]. Macrophages
are an important source of thymic renin and Ang II in rats [163].
Upregulation of the RAS in macrophages and immune cells may be
particularly important in conditions associated with vascular injury
and inammation, such as in diabetes, atherosclerosis and hypertension. It should be stressed that these data derive predominantly
from experimental models and the signicance in humans remains
unclear.

8. The vascular RAS and hypertension


The potential role of a non-circulating RAS in the pathogenesis
of hypertension was suggested when it was reported that inhibitors
of the RAS can lower blood pressure in hypertensive patients whose
plasma renin levels are normal or even low [36]. This was further observed in experimental studies, which demonstrated that
chronic administration of ACE inhibitors or angiotensin II receptor
blockers lower the blood pressure in various hypertensive animal
models where activity of plasma renin is not elevated [103]. In
such models with normal/low PRA, ACE activity is increased in
the vasculature and vasoconstrictor responses to Ang I are augmented suggesting that increased Ang II levels are present in the
vessel wall. Hyperactivation of the vascular RAS may contribute
to the pathophysiology of hypertension by increasing vascular
tone through direct vasoconstrictor, pro-inammatory, pro-brotic
and hypertrophic effects of Ang II and by increased local sympathetic activity, independently of circulating Ang II [34,35,120]. SHR
exhibit increased vascular renin activity [7].
The exact role of circulating versus vascular RAS in the maintenance of blood pressure is unclear. Some studies showed that
vascular RAS is critically involved in maintaining chronic two kidney, one clip hypertension [103], whereas others showed that
circulating, but not extra-renal RAS, is important in maintaining
blood pressure in Goldblatt hypertension [122]. In this model of
hypertension, vascular RAS regulation is independent of circulating
Ang II [122].
The (patho)physiological signicance of the vascular RAS in
clinical hypertension is unclear and little is known about renin
and angiotensinogen status in human intact vessels. However,
patients with hypertension have increased vascular responses to
exogenous Ang II [106,135] and we demonstrated that in cultured vascular smooth muscle cells from resistance arteries of
hypertensive patients, signaling by Ang II through AT1 receptors
is signicantly enhanced [152154]. These ndings are similar to
those in SHR indicating hyperactivation of the vascular RAS in
hypertension [103]. Moreover, hypertensive patients treated for
one year with ACE inhibitors or ARBs, but not with atenolol (beta
blocker), exhibited signicant regression of vascular remodeling
[87,132,133]. These processes were independent of hemodynamic
changes, because ACE inhibitors, ARBs and atenolol reduced blood
pressure to similar levels, suggesting a local effect of RAS inhibition
[87,132,133]. Chronic ARB treatment in hypertensive patients was
associated with increased expression of AT2 receptors in resistance
arteries [130], which could contribute to improved vascular function and regression of vascular remodeling in these patients [130].
Taken together, these clinical data, albeit indirect, suggest a functional local RAS, which may be important in vascular regulation in
human hypertension.

A. Nguyen Dinh Cat, R.M. Touyz / Peptides 32 (2011) 21412150

2147

9. The (patho)physiological signicance of the vascular RAS


further considerations

might provide better therapeutic outcomes in patients with Ang


II-dependent cardiovascular diseases.

Despite extensive data supporting a functional vascular RAS


there are a number of issues that warrant further consideration.
Firstly, many studies identifying the tissue RAS were performed
in in vitro conditions, where the RAS was investigated in isolated vessels or vascular beds ex vivo or in cultured endothelial
and vascular smooth muscle cells. Cultured cells, and particularly
immortalized cell lines, may differ phenotypically from cells in
intact vessels in vivo. In many of those studies, Ang II production was evaluated in conditions in which the RAS enzymes were
up- or down-regulated by genetic or pharmacological manipulation. Secondly, in many animal studies, activation of the vascular
RAS was performed in mice in which renin and/or angiotensinogen was overexpressed in a vascular-specic manner, making it
difcult to interpret the physiological signicance of endogenous
RAS enzymes and peptides at the local vascular level. Thirdly, one
of the major challenges in studying the role of vascular RAS in
whole animals is being able to differentiate, in an intact system,
the local tissue system from the circulating/systemic system. Elegant novel approaches to study tissue RAS in whole animals have
recently been developed. Reudelhuber [118] has revolutionized
the eld by creating a peptide-releasing protein that facilitates
the precise targeting of peptide production in a tissue-specic
manner. For example, linking the fusion protein to specic gene
control elements (promoters) that target vascular genes results
in the expression of the transgene in vessels and the release of
Ang II (or its peptides) into the vessel wall. Using this fusion protein engineered to release peptides from specic cell-types will
elucidate the (patho)physiological role of Ang peptides in a tissuerestricted manner in whole animals over the long-term. Finally,
demonstration that the vascular/tissue RAS is activated and that
it participates in the regulation of vascular function in humans
has yet to be demonstrated. This is highlighted in clinical studies where anephric patients failed to demonstrate any circulating
renin although Ang I, Ang II, and Ang III were detectable in very
low concentrations indicating a non-specic extra-renal source
[162].

Conicts of interest

10. Conclusions
The global RAS comprises a dual system: circulating RAS and
tissue RAS [69,108,116]. The vascular autocrine/paracrine RAS
may function primarily in controlling vascular tone, whereas the
endocrine circulating RAS may be more important in regulating
short-term cardiovascular-renal homeostasis. All tissues important
in cardiovascular regulation, as well as tissues unrelated to blood
pressure control, e.g. pancreas and gut, possess a local RAS. Exact
functions of the local RAS are unclear but probably contribute to
regional tissue control. Functionally tissue-based RAS may amplify
actions of circulating Ang II. Most components of the RAS, including angiotensinogen, ACE, Ang I and Ang II are expressed in the
vascular system. However it still remains elusive as to whether
renin is synthesized in the vessel wall or whether it is taken up as
kidney-derived renin from the circulation. There have been three
major developments in the eld of the vascular RAS that need to
be highlighted: (1) the ndings that in addition to the classical
components of the RAS, (P)RR, novel Ang peptides and ACE2 are
present in the vessel wall, (2) cells of the immune/inammatory
system may contribute to Ang II in the vessel wall, and (3) activation of the RAS in perivascular adipose tissue may contribute
to the vascular RAS and inuence vascular function. Interventions
targeting both the systemic and the vascular RAS should facilitate
more complete inhibition of the RAS, which in the clinical setting

None.
Acknowledgements
Work from the authors laboratory was supported by grants
44018 and 57886, both from the Canadian Institutes of Health
Research (CIHR). RMT is supported through a Canada Research
Chair/Canadian Foundation for Innovation award. CAN is supported
through a fellowship from the CIHR.
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