Clinical Science (2016) 130, 9–18 doi: 10.

1042/CS20150654

Sex, the brain and hypertension: brain oestrogen

receptors and high blood pressure risk factors
Meredith Hay*

*Department of Physiology, Evelyn F. McKnight Brain Institute, Saver Heart Center, University of Arizona, Tucson, AZ, U.S.A.

Abstract
Hypertension is a major contributor to worldwide morbidity and mortality rates related to cardiovascular disease.
There are important sex differences in the onset and rate of hypertension in humans. Compared with age-matched
men, premenopausal women are less likely to develop hypertension. However, after age 60, the incidence of
hypertension increases in women and even surpasses that seen in older men. It is thought that changes in levels
of circulating ovarian hormones as women age may be involved in the increase in hypertension in older women. One
of the key mechanisms involved in the development of hypertension in both men and women is an increase in
sympathetic nerve activity (SNA). Brain regions important for the regulation of SNA, such as the subfornical organ,
the paraventricular nucleus and the rostral ventral lateral medulla, also express specific subtypes of oestrogen
receptors. Each of these brain regions has also been implicated in mechanisms underlying risk factors for
hypertension such as obesity, stress and inflammation. The present review brings together evidence that links
actions of oestrogen at these receptors to modulate some of the common brain mechanisms involved in the ability
of hypertensive risk factors to increase SNA and blood pressure. Understanding the mechanisms by which
oestrogen acts at key sites in the brain for the regulation of SNA is important for the development of novel,
sex-specific therapies for treating hypertension.

Key words: blood pressure, central nervous system, oestrogen, PVN, RVLM, sex, SFO.

INTRODUCTION
Hypertension is a worldwide health challenge and a key factor in
the morbidity and mortality related to cardiovascular disease [1].
Sex differences in the rate and onset of hypertension have been
well established. In both women and men, there is an age-related
increase in blood pressure (BP). However, women under the age
of 50 have a lower incidence of hypertension than age-matched
men [2,3]. After age 55, the incidence of hypertension in women
markedly increases and almost 70 % of women aged over 65 in
the U.S.A. are hypertensive [4]. Contributing risk factors to the
development of hypertension as women age include changes in
levels of circulating ovarian hormones [5,6], obesity [7–10], salt
intake [11–13], stress [14,15] and the immune system [16].
One mechanism that is common to all these hypertensive risk
factors is an increase in sympathetic nerve activity (SNA). The
central nervous system (CNS) regulation of SNA, heart rate and
ultimately BP involves a number of key brain regions in the hy-
pothalamus and brain stem, including the nucleus of the solitary
tract (NTS), nucleus ambiguus, area postrema, caudal ventrolat-
eral medulla (CVLM) and rostral ventrolateral medulla (RVLM),
parabrachial nucleus (PBN), the subfornical organ (SFO) and the
paraventricular nucleus of the hypothalamus (PVN). All these
regions of the brain are known to express oestrogen receptors
(ERs), and oestrogen modulation of these neurons and associated
glia and oestrogen modulation of brain neurotransmission have
been shown to decrease SNA and decrease BP [17]. The present
review surveys the current understanding of the role of increased
SNA in the risk factors contributing to hypertension and the role
of ERs in the brain on the regulation of SNA, and attempts to
shed some possible mechanistic light on how ovarian sex steroid
actions on discrete brain regions responsible for the regulation of

Abbreviations: ACTH, adrenocorticotrophic hormone; Aldo, aldosterone; AngII, angiotensin-II; AT1, AngII type 1; BMI, body mass index; BP, blood pressure; CEE, conjugated equine
oestrogen; CNS, central nervous system; CO, cardiac output; CRF, corticotrophin-releasing factor; CVLM, caudal ventrolateral medulla; ER, oestrogen receptor; ERT, oestrogen
replacement therapy; GluN1, glutamate-receptor subunit 1; HPA, hypothalamic–pituitary–adrenal; HRT, hormone replacement therapy; MAPK, mitogen-activated protein kinase; NMDA,
N-methyl-D-aspartate; NO, nitric oxide; nNOS, neuronal nitric oxide synthase; NTS, nucleus of the solitary tract; OC, oral contraceptive; OVX, ovariectomized; PBN, parabrachial nucleus;
PVN, paraventricular nucleus; ROS, reactive oxygen species; RVLM, rostral ventral lateral medulla; SFO, subfornical organ; SNA, sympathetic nerve activity; WT, wild-type.

Correspondence: Meredith Hay (mhay@arizona.edu).


C 2016 Authors; published by Portland Press Limited 9
 M. Hay
SNA may attenuate the development of hypertension. An under-
standing of these mechanisms and their contribution to this dev-
astating disease are essential to the development of sex-specific
therapies for treatment and management of hypertension.
SEX, OVARIAN HORMONES AND
SYMPATHETIC OUTFLOW
Although it is well known that increases in SNA result in in-
creases in vasomotor tone [18,19], the correlation between rest-
ing sympathetic outflow and resting arterial BP in humans is
not what would be expected. In studies of both young men and
young women in which direct recordings of SNA were obtained
in awake individuals, those with a higher SNA were found to have
lower resting BP than those with a lower SNA [20,21]. In young
men, this higher SNA correlates with lower cardiac output (CO)
[19], thus explaining the normal BP in the presence of higher
SNA in young men. However, in young women the correlation
of SNA, vascular tone and CO is absent [20,22]. Further studies
have found that young women have enhanced vascular β-receptor
function [23], which is thought to offset the increased SNA seen
in them [24]; thus this may contribute to the maintenance of
normal BP in young women. These sex differences in the rela-
tionship between SNA and BP is lost as women enter menopause.
In studies examining SNA in older women, a tight correlation was
found between SNA and BP [21]. It has been suggested that de-
creases in circulating ovarian hormones may modulate vascular
β-receptor expression, thus unmasking the vasoconstrictor ef-
fects of increased SNA. Therefore, the postmenopausal increase
in sympathetic outflow in women most probably contributes to
the increased incidence of hypertension in women aged over 50.
Studies on the effects of ageing on SNA and BP in women have
found that, independent of the menopause, there is an increase in
SNA as women age [25]. In that study, for each decade increase
in life, women exhibited significantly greater increases in resting
SNA compared with age-matched men. For both older men and
older women, there is a positive correlation between SNA and
BP, with this correlation being much stronger in older women.
In addition, older women have been shown to have an impaired
baroreflex function compared with younger women [26]. These
results, together, suggest that an increase in SNA may be a key
factor in the development of hypertension as women age.
The effects of oral contraceptives (OCs) and hormone replace-
ment therapy (HRT) on resting BP and SNA have been examined
in a number of studies [27–31]. With regard to OCs, these studies
support the conclusion that their use increases the risk of hyper-
tension. This conclusion would suggest that OC use would also
result in an increase in resting SNA. To test this hypothesis, a
recent study examined the interrelationship of resting arterial BP,
SNA, total peripheral resistance (TPR) and CO in two groups of
women between the ages of 18 and 35, either taking OCs or not
[32]. The women taking OCs had a higher BP compared with
the women not taking OCs, but both groups had similar levels of
SNA. This result was unexpected given the higher resting BP in
the women taking OCs. One mechanism suggested as possibly
contributing to the lack of change in SNA in the presence of in-
10 
C 2016 Authors; published by Portland Press Limited
creased BP is that OCs may result in a blunting of the baroreflex
regulation of BP. However, further studies are needed to test this
hypothesis fully.
With regard to HRT and changes in SNA and BP, the results
are less clear [29–31]. Factors that influence the effects of HRT on
the regulation of BP include the age of the woman when she starts
HRT, the type of hormone being used as a replacement, how the
HRT is taken (oral vs transdermal) and any predisposing factors
for hypertension that may exist in the individual [6,31]. Results
include the finding of the Women’s Health Initiative (WHI) trial
that hormone replacement with conjugated equine oestrogens
(CEEs) results in a small increase in BP [33]. However, other
studies have shown that CEEs result in a lower BP after 10 years
of treatment [34]. It has been suggested that the method of HRT
delivery influences CEEs’ effects on BP. Orally taken oestrogens
have been shown to increase or have no effect whereas trans-
dermal oestrogens reduce SNA and BP [29]. The role of the
brain, and consequently the SNA, in the effects of HRT on BP
control in experiments on direct recordings of muscle SNA have
been more conclusive. In studies in postmenopausal women, it
was found that transdermal but not oral estradiol significantly
decreased SNA and had minimal effects on the BP [30,35]. It
has been suggested that estradiol’s effect to decrease SNA is due
to oestrogen’s direct effect on CNS regions known to regulate
SNA.
BRAIN OESTROGEN RECEPTORS,
SYMPATHETIC OUTFLOW AND BLOOD
PRESSURE REGULATION
Using animal models of hypertension, we have gained somewhat
more clarity on the CNS mechanisms that may underlie the effects
of oestrogen replacement on SNA and BP.
Earlier results from my laboratory have shown that brain ER
activation in key regions known to be important for the regulation
of SNA are able to protect against hypertension induced by either
angiotensin-II (AngII) or aldosterone (Aldo) [36–38]. In both
males and ovariectomized (OVX) females, central administration
of oestrogen attenuates AngII- or Aldo-induced hypertension.
But, identification of the sites of action of oestrogen in the brain
and the central cellular mechanisms required for oestrogen to
modulate the development of neurogenic hypertension are still
being elucidated.
The rostral ventral lateral medulla
A key area of the brain stem in regulation of SNA and thus BP is
the RVLM. In both human and animal studies, increases in RVLM
activity are known to be associated with SNA and SNA-related
changes in BP [39–43]. The RVLM expresses both ERα and
ERβ receptors [44], and activation of these receptors via direct
injection of oestrogen into the RVLM results in a decrease in
SNA [45]. Importantly, however, it is the ERβ receptors and not
the ERα receptors within the RVLM that contribute to estradiol’s
ability to inhibit increases in SNA and BP [46,47] caused by
AngII or Aldo. Recent studies selectively knocked down ERβ
receptors in the RVLM using siRNA in intact female rats, in which
Brain oestrogen receptors and high blood pressure risk factors
infusion of Aldo has a minimal effect on SNA and BP compared
with OVX females or males [36]. However, after knockdown
of ERβ receptors within the RVLM, Aldo results in significant
hypertension in intact females [47]. These results support the
conclusion that oestrogen acting on ERβ receptors in the RVLM
may be partially responsible for oestrogen’s protection against
some forms of hypertension.
Sex differences in the expression of both AngII type 1 (AT1)
receptors and NADPH oxidase subunits have been identified in
the RVLM [48]. NADPH oxidase is the key enzyme involved
in reactive oxygen species (ROS) production and known to be
essential for the development of AngII-dependent hypertension
[49]. Using electron microscopy and immunolabelling in males,
female rats in pro-oestrus and female rats in di-oestrus, the fe-
males were found to have more AT1 labelling in the dendrites
of the RVLM compared with males, but less NADPH oxidase
p47 subunit labelling [48]. In addition to the sex differences in
ROS signalling in the RVLM, there are also suggestions that there
are important sex differences in RVLM neurotransmission [50].
Glutamate neurotransmission and activation of the N-methyl-D-
aspartate (NMDA) receptor within the RVLM is known to be
important in RVLM modulation of BP [50]. Changes in the sub-
cellular trafficking of the glutamate-receptor subunit 1 (GluN1) of
the NMDA receptor is related to increases in both RVLM activ-
ity and SNA [50]. Recent studies have shown that a low-dose
infusion of AngII which increases blood pressure in males also
results in an increase in trafficking of GluN1 in RVLM neurons
of males but not females. This sex difference in AngII-induced
excitatory neurotransmitter receptor trafficking at the level of the
RVLM is most probably a key cellular mechanism underlying sex
differences in AngII-dependent hypertension.
The subfornical organ
Another region of the brain known to be important in the reg-
ulation of SNA is the subfornical organ (SFO), which is a cir-
cumventricular organ in the forebrain that is directly involved
in the ability of circulating AngII to increase SNA, resulting in
neurogenic hypertension. Studies in animal models have shown
that increasing circulating AngII results in increases in SFO neur-
onal activity, which then increases SNA via the SFO projections
to the paraventricular nucleus (PVN) [51,52]. An important cel-
lular mechanism known to be involved in AngII activation of
SFO neurons and the associated increase in SNA and BP is AT1
receptor-induced increases in cellular ROS [49,53]. Blockade of
the formation of ROS inhibits activation of SFO neurons and the
development of AngII-dependent hypertension [54,55]. In studies
using brain slices of the SFO from male mice, AngII-induced pro-
duction of ROS in these neurons was blocked by pre-incubation
of the tissue with estradiol, suggesting that oestrogen can inhibit
AngII-induced ROS production [56].
In addition to AngII receptors, ERs are known to be expressed
in the SFO and have been identified on the same neurons that
express AT1 receptors [57]. Unlike the RVLM, the SFO predom-
inately expresses ERα receptors [44]. Activation of SFO ERs has
been shown to decrease the baseline SFO neuronal activity and in-
hibit SFO neuron activation by AngII [58]. Recent studies tested
the hypothesis that it is the ERα receptors in the SFO that are re-
sponsible for oestrogen’s protective effects against AngII-induced
hypertension [59]. These studies employed selective knockdown
of the ERα receptor in the SFO using adenovirus-Cre injected
into the SFO of ERα flox mice. In the animals that had the ERα
receptor knocked down selectively in the SFO, AngII induced a
significantly greater increase in both the hypertensive response
and the SNA, as measured by ganglionic blockade, than seen in
control animals. These results suggest that the ERα receptors in
the SFO are required to protect against the increase in SNA and
BP caused by AngII.
The paraventricular nucleus
The PVN in the hypothalamus is a key region of the brain involved
in the regulation of SNA. It is the parvocellular neurons of the
PVN that receive neuronal input from the SFO, and then relay
this information to the RVLM and the interomedial column of
the spinal cord region, which controls SNA.
The study of the role and effects of oestrogen in the modulation
of PVN activity, and subsequent modulation of SNA and BP,
started only recently. Although both ERα and ERβ receptors
have been reported as expressed in the PVN, it is the ERβ ones
that seem to be more predominantly expressed and play a major
role in the modulation of the PVN [60,61]. In an Aldo-induced
model of hypertension, blockade of the ERβ receptors in the
PVN using siRNA knockdown results in an increase in SNA and
BP during Aldo infusion compared with sham injections [47],
suggesting that, in the PVN, ERβ receptor activation protects
intact females against some types of hypertension.
Only recently have the cellular and molecular mechanisms
within the PVN that underlie these protective effects of ERβ
receptor activation started to be studied. Both ROS and nitric ox-
ide (NO) mechanisms have been implicated [17,62,63]. In recent
studies using male and female mice in which the AT1 receptor
was co-localized with green fluorescent protein in the PVN [63],
the effects of AngII infusion on BP and ROS production in the
PVN’s AT1-positive cells was determined. As has been shown
previously [37], AngII infusion resulted in a significant increase
in BP in the males but not in the intact females. Importantly,
this increased BP in the males was associated with a greater
production of ROS in these cells compared with intact females,
suggesting that AngII induces an increase in ROS production in
the PVN of males but not intact females.
In studies in which the PVN of male rats was directly stim-
ulated with glutamate injections [64], oestrogen acting at ERβ
receptors in the PVN has been shown to inhibit the sympatho-
excitatory and hypertensive effects of glutamate activation in the
PVN. Furthermore, the ability of oestrogen to inhibit activation
of the PVN depends on NO production, suggesting that estradiol
inhibition of SNA at the level of the PVN requires oestrogen ac-
tivation of NO production [64]. The role of NO in AngII-induced
increases in SNA and BP has been demonstrated to be import-
ant in intact female mice but not in males [65]. In these studies,
central blockade of NO production via cerebral infusion of N G -
nitro-L-arginine methyl ester (L-NAME) resulted in an increase
in the AngII-induced increase in SNA and BP in intact females
but not in intact males. Furthermore, intact females have a higher
resting level expression of neuronal NO synthase (nNOS) within

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 M. Hay
the PVN compared with males and OVX females. Together, these
studies suggest that sex differences in AngII hypertension involve
an effect of oestrogen on the increased NOS and NO inhibition
of PVN activation, as well as oestrogen suppression of an AngII-
induced increase in ROS in the PVN.
As reviewed above, an important role for the ERα and ERβ
receptors in specific regions of the brain known to be important in
the regulation of SNA and hypertension has been established in
animal models. What is less clear is why some of these brain re-
gions express primarily ERα and others ERβ receptors, and how
these specific ERs may selectively modulate neurotransmission
in these brain regions. Are these differences in ER expression in
the brain also seen in humans? A common cellular mechanism,
regardless of the site of the brain region expression, includes in-
hibition of ROS formation and enhancement of nNOS expression
[63,64]. How we might exploit this understanding of selective ex-
pression of ERs in these key brain regions involved in hyperten-
sion, to develop ER-selective drugs to treat hypertension, needs
further study.
OBESITY, OESTROGEN AND SYMPATHETIC
OUTFLOW
In western countries, the increases in population rates of altered
metabolic conditions involved in obesity, hypertension, insulin
resistance and dyslipidaemia have together been referred to as the
metabolic syndrome [66]. It is estimated that approximately 25 %
of adults in the U.S.A. have been predicted as having the meta-
bolic syndrome, which is associated with a significantly higher
rate of death due to related cardiovascular disease [67,68]. An un-
derstanding of the underlying mechanisms associated with this
high rate of mortality from the metabolic syndrome is critical
to improving the health of both women and men. The increase
in the incidence of hypertension in obese individuals has shown
good correlation with an increase in SNA and related end-organ
damage [8,69]. Specifically, this increase in obesity-related hy-
pertension correlates highly with levels of visceral adiposity but
not subcutaneous adiposity [70,71]. However, most of these data
on the relationship between obesity and SNA have been obtained
from either obese men or male animal models. The study of the
role of sex and sex steroids, and how obesity and the metabolic
syndrome may affect SNA and hypertension in women, started
only recently [72].
In a study examining SNA, BP and body mass index (BMI)
in age-matched men and women, women with hypertension had
an increase in SNA compared with the non-hypertensive control
females, but this increase in SNA was not related to BMI [10].
This is in contrast to age-matched hypertensive men whose SNA
was the same as that in normotensive men, but directly related
to their BMI. This study also measured plasma leptin levels and
observed that women in this study had higher circulating levels of
leptin compared with the men. These results are consistent with
other reports that show females having higher levels of circulating
leptin than males [73].
Leptin is a hormone important to energy homoeostasis and
involved in regulation of feeding behaviours, as well as SNA in-
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nervation of brown adipose and renal and lumbar SNA [26,74,75].
Leptin has been shown in men and male animal models to induce
increases in SNA and result in an increase in BP. New and in-
triguing studies in an animal model [76] have shown, in female
animals, that the effects of leptin on renal, splanchnic and lumbar
SNA depends on the levels of estradiol. In this elegant set of stud-
ies [26,74,75], SNA in intact and OVX female rats was measured
in a number of different sympathetic areas, each important for the
regulation of BP. Leptin was infused directly into the lateral vent-
ricles of the brain and the effects on SNA measured. Centrally
administered leptin was able to increase only lumbar and renal
SNA when oestrogen was surging systemically (pro-oestrus in
the intact rats) or during exogenous estradiol infusion in the OVX
rats. These results offer an interesting and intriguing interaction
between central leptin levels and ERs, and suggest that surges in
oestrogen may be required to unmask leptin’s sympathoexcitatory
effects in females. However, there are some limitations to these
studies with regard to how they may inform our understanding
of the role of leptin in hypertensive obese women. First, in these
studies in female rats, leptin was infused directly into the cerebral
ventricles at doses much higher than observed in premenopausal
women [10]. Second, it is known that both lean and obese pre-
menopausal women have a lower SNA than age-matched men,
despite having higher levels of circulating leptin [10]. Thus, the
role of leptin in the regulation of SNA in premenopausal women
may be less robust than that observed in animal models. Further-
more, how this relationship between leptin and SNA may change
as women age and the effect of menopause on this relationship
are areas that needs further study.
Study of exactly where in the brain this interaction between
leptin and SNA takes place and what types of ERs are involved is
only just starting. The expression of the leptin receptor, ObR, has
been identified throughout the mammalian brain, including sites
in the lateral hypothalamus [77], and key areas involved in the
regulation of SNA, including the SFO [78] and the NTS [79]. In
studies where the ObR leptin receptor was knocked down in the
SFO of male mice, the sympathoexcitatory effects of centrally
administered leptin were eliminated, suggesting that, in males,
leptin’s actions to increase SNA need the SFO. But no such stud-
ies of the effects of leptin on the SFO have been performed in
females. We do know that the SFO expresses predominantly ERα
receptors [44], and that activation of ERα receptors in the SFO
has been shown to decrease SFO neuronal activity [58] and atten-
uate AngII-induced increase in SNA and BP [59]. But, we also
know that, in female animal models, the sympathoexcitatory ef-
fects of leptin are seen only when circulating oestrogen levels are
high [76]. Thus, one might hypothesize that either leptin activa-
tion of ObR in the SFO, which increases SFO-induced increases
in SNA, and activation of ERα receptors in the SFO, which in-
volves inhibition of SNA, involve separate pathways and separate
signalling mechanisms within the SFO, or the oestrogen-induced
facilitation of leptin sympathoexcitatory effects masks the sym-
pathoinhibitory effects of oestrogen alone. Such ObR and ERα
receptor interactions at the level of the SFO are only speculative
and most certainly require further experimentation and study.
A second possible site of brain interaction of leptin and oes-
trogen to regulate SNA is the PVN. In recent studies in fe-
Brain oestrogen receptors and high blood pressure risk factors
male rats, in which α-melanocyte-stimulating hormone (α-MSH)
receptors in the PVN were blocked using nanolitre injections of
the selective MC3/4 receptor antagonist SHU9119, the sympath-
oexcitatory effects of central leptin in female rats in pro-oestrus
were eliminated [76]. These results suggest that, in addition to
the SFO, the PVN may be a key site of integration of leptin and
ERs in the modulation of SNA and BP.
Although the molecular mechanisms involved in oestrogen’s
modulation of leptin’s central sympathoexcitatory effects are not
yet known, a possible candidate would be a direct interaction
between the leptin ObR and ERs. ER modulation of ObR has
been well described in other tissues, including bone [80], cancer
cells [81] and the hypothalamus [82], in which activation of ERα
receptors induces the expression of ObR via activation of the
extracellular signal-related kinase (ERK)1/2 [mitogen-activated
protein kinase (MAPK)1/MAPK3] signalling pathway. Future
studies are needed to determine if this molecular regulation of
ObR by ERα receptors is involved in the ability of leptin to
increase SNA in females only when oestrogen levels are high.
STRESS, THE BRAIN AND HYPERTENSION
Both acute and chronic stress are major risk factors in the devel-
opment of cardiovascular disease, and increases in SNA and hy-
pertension [83,84]. Stress activates the hypothalamic–pituitary–
adrenal (HPA) axis, and corticotrophin-releasing factor (CRF)-
containing neurons in the PVN stimulate adrenocorticotrophic
hormone (ACTH) release from the anterior pituitary and an in-
crease in glucocorticoid and catecholamine release from the ad-
renal gland [85,86]. Stress-induced increases in SNA are also
thought to involve CRF-containing neurons in the PVN that in-
nervate and activate neurons in the RVLM to increase SNA.
Furthermore, direct injections of CRF into the RVLM results in
increases in lumbar SNA [86] and BP [87]. Together, the peri-
pheral increase in catecholamine release from the adrenal gland
and the increase in SNA result in an increase in BP and hyper-
tension.
When compared with premenopausal women, postmeno-
pausal women have been shown to have an increased HPA re-
sponse and BP response to mental stress [88,89]. Furthermore,
this increased HPA activation in postmenopausal women is blun-
ted by estradiol replacement [88,89]. In animal models sex dif-
ferences in response to stress and ACTH release have been well
documented [90–93].
However, the effects of oestrogen on the HPA axis, the site of
action in the brain and oestrogen’s role in modulating the SNA
response to stress are still controversial. A number of studies in
animal models have shown that ovariectomy attenuates stress-
induced increases in circulating corticosteroids and ACTH, and
that oestrogen replacement reverses these effects [91,92]. Other
studies have shown no effect of oestrogen on measures of the
HPA axis [94] and still others have shown, similar to the early
studies in women, that oestrogen replacement inhibits stress-
induced increases in ACTH [93,95,96].
Oestrogen’s site of action within the brain for modulating
stress-induced activation of the HPA axis and SNA is still not
clear. One possible site suggested is the PVN [93]. In studies us-
ing two different types of stress and c-fos measurement of PVN
activation, it was found that, in OVX rats, oestrogen replacement
increases plasma corticosteroid response to stress but inhibits
ACTH-induced stress levels [93], and oestrogen replacement was
found to inhibit stress-induced activation of the PVN. In contrast,
studies using intact females and males found the former had an
enhanced ACTH response to stress and enhanced c-fos-measured
PVN activation compared with males [94], but found no role for
oestrogen in this response. Some of these differences in the results
from the animal studies, and how they correlate with data from
women, have suggested the importance of the timing of meas-
urements in the intact animals and the methods of how and when
estradiol should be replaced in the OVX animals [96]. Oestrogen
replacement therapy (ERT) in women uses low, chronic and re-
latively stable levels of oestrogen. In an attempt to mimic ERT
in women, an animal study using chronic, low-level oestrogen
replacement in mature female rats found that oestrogen inhib-
its both noise stress- and inflammation stress-induced increases
in ACTH [96]. Furthermore, this study also found that chronic
oestrogen replacement inhibits noise stress-induced increases in
the activation of both PVN neurons and selective catecholamine-
containing neurons in the ventrolateral medulla. These results
suggest that chronic low-level oestrogen replacement in an an-
imal model does inhibit stress-induced activation of the HPA axis
and key neuronal regions involved in SNA increases.
One cellular mechanism that may underlie oestrogen’s ability
to modulate CRF-containing PVN neurons is by altering neur-
onal excitability. In electrophysiological experiments using rat
brain slices of the RVLM projecting PVN neurons, the effects of
short-term oestrogen replacement on PVN neurons were meas-
ured [97]. In these experiments, OVX rats were replaced with
oestrogen using daily, high-dose, subcutaneous injections of oes-
trogen for 4 days; then PVN brain slices were obtained and the
potassium current measured. It was found that oestrogen can
decrease both the expression and the current density of the po-
tassium IA current. It is interesting that an inhibition of IA current
density would be expected to increase PVN excitability, which is
not what was seen when OVX females were replaced with con-
stant, low-dose, long-duration oestrogen replacement. It remains
to be tested whether, if oestrogen is replaced in an animal model
similar to that for postmenopausal women, the effects on PVN
potassium currents would be different.
In addition to the PVN, the RVLM neurons receiving CRF-
containing PVN terminals are thought to be important for stress
activation of SNA and hypertension. If stress increases the activity
of CRF-containing PVN neurons, then it would be reasonable to
hypothesize that this would, in turn, result in increases in CRF
activation and RVLM activation, and a subsequent increase in
SNA. Studies on OVX rats using c-fos as a measure of cellular
activation have shown that stress activation of catecholamine-
containing ventrolateral cells is inhibited by long-term, low-dose,
constant oestrogen replacement [96]. However, these data were
not linked to changes in the SNA or BP. Thus, there is some
evidence to suggest that oestrogen may inhibit stress activation
of RVLM neurons, although direct evidence that this mechanism
is linked to stress-induced increase in SNA and BP has yet to be
established.

C 2016 Authors; published by Portland Press Limited 13
 M. Hay

Figure 1 A hypothesis about how hypertensive risk factors such as obesity, stress and inflammation modulate common
central regions of the brain, such as the SFO, PVN and RVLM, causing increases in SNA and BP
It has been suggested that obesity, possibly through leptin-related actions, increases SNA via actions at the SFO and PVN.
In females, this sympathoexcitatory effect of leptin requires high levels of circulating oestrogen. It has been suggested
that stress, activating the HPA axis, increases SNA and BP via actions at the CRF-containing PVN neurons and RVLM.
Evidence suggests that oestrogen may attenuate stress-induced increases in SNA by reducing stress activation of the
PVN and RVLM. It has been suggested that increased inflammation and T-cell activation increase BP partially through an
increased SNA. The T-cell innervation into the SFO in males but not in females in AngII-induced hypertension has been
hypothesized as being involved in inflammation-related hypertension. Oestrogen, acting at specific receptors within the
SFO, PVN and RVLM, is hypothesized as inhibiting the ability of some of these hypertensive risk factors and their respective
mechanisms to increase SNA, and thus attenuate the development of hypertension.

SEX, INFLAMMATION AND HYPERTENSION
One of the most recent advances in our understanding of under-
lying factors that influence the development and prevalence of
hypertension is the role of the adaptive immune system in the de-
velopment of high BP. In both hypertensive humans and animal
models, T-cells have been shown to accumulate in the kidneys
and vasculature [16]. In initial studies in which male mice lacking
lymphocytes due to a deficiency in the recombination-activating
gene (Rag-1−/− ) were infused with AngII, the level of hyper-
tension was significantly less than that observed in wild-type
(WT) mice [98]. However, when T-cells from a male donor were
given back to the male Rag-1−/− mice, the hypertensive effects of
AngII were restored, suggesting that AngII-induced hypertension
requires the adaptive immune system, and T-cells in particular.
This role of T-cells and the adaptive immune system has also been
seen in a number of other models of hypertension in male animals
[99,100]. The role of the sympathetic nervous system, and renal
sympathetic nerve innervation of the kidney in particular in this
immune-mediated hypertension, has been shown in an elegant
new study in male mice [101]. This study tested the hypothesis
that the activation of the immune system during AngII hyper-
tension depends on renal sympathetic innervation. Bilateral renal
denervation not only attenuated AngII hypertension in these mice
but also reduced AngII-induced, T-cell infiltration of the kidney.
Unfortunately, this study used only male mice and did not offer
any insights into the role of renal SNA in inflammation-induced
AngII hypertension in female mice.
Only recently has the study of the role of sex and sex hormones
in the effect of the adaptive immune system on BP regulation
started [102–105]. Recent studies have found that the role of the
adaptive immune system in the development of AngII hyperten-
sion depends on both the sex of the T-cell [104] and the sex of the
animal receiving T-cell replacement [103]. In a study using intact
female Rag-1−/− mice, it was found that, after adoptive transfer
of WT male T-cells into the intact females, the females were pro-
tected from AngII hypertension and showed significantly lower
BP after AngII infusion compared with male Rag-1−/− mice that
had also received WT male T-cell transfer [103].
The sex of the T-cell is also known to be important in this
model of inflammation-induced AngII hypertension [104]. A re-
cent study has shown that, when male Rag-1−/− mice are given

14 
C 2016 Authors; published by Portland Press Limited
Brain oestrogen receptors and high blood pressure risk factors
T-cells from WT female donors, they do not develop the same
level of hypertension after AngII infusion as male Rag-1−/− mice
given T-cells from WT male donors [105]. These results suggest
that not only is the sex of the host important, but a critical determ-
inant in the development of inflammation-induced hypertension
is also the sex of the T-cell [105].
The role of the sympathetic nervous system in this protection
in females against inflammation-induced AngII hypertension has
not yet been determined. However, the above referenced stud-
ies [103–105], also using male and female Rag-1−/− mice, did
observe a significant increase in T-cell infiltration into the SFO
in the male Rag-1−/− mice compared with the female Rag-1−/−
mice. These results suggest that T-cell infiltration into the SFO
may be important to inflammation-induced AngII hypertension.
Additional studies are needed to investigate the role of ovarian
hormones in inflammation-induced hypertension and the effect
of ovarian hormones on T-cell infiltration into key end-organs
such as the kidney, vasculature and brain.
CONCLUSION
The present review links compelling evidence for the role of the
brain in the effects of sex and sex hormones on the regulation of
SNA and the development of hypertension. Specific regions of the
brain known to be required for the development of neurogenic
hypertension, such as the SFO, PVN and RVLM, also express
ERs. Each of these key regions express unique populations of
ERs, either ERα or ERβ or both, and the activity of the neurons
in these regions can be affected by selective ER modulators.
There is significant evidence from animal models to support the
conclusion that activation of these key brain ERs can modulate
cell activation in these regions, and alter the responses of these
neurons to hormones, peptides and neurotransmitters known to
be involved in increases in SNA and BP.
The present review also, for the first time, endeavours to link
some common mechanisms underlying known hypertensive risk
factors of obesity, stress and inflammation. Figure 1 illustrates
how the risk factors of obesity, stress and inflammation all have
verified links to the SFO, PVN or RVLM to increase SNA, and
result in hypertension. In each of these brain regions there is
compelling evidence to support oestrogen acting on selective re-
ceptors in these key regions to modulate increases in SNA caused
by the risk factors, and thus decrease the probability of hyper-
tension. In some cases such as obesity, it is hypothesized that
circulating oestrogen may facilitate leptin-induced increases in
SNA and hypertension. The sites in the brain involved in this
interaction between leptin and oestrogen have not been proven
but may include both the PVN and the SFO. In other cases, such
as stress-induced increases in SNA, oestrogen is hypothesized to
act on the PVN and RVLM to reduce stress-induced activation
of these regions, and thus attenuate stress-induced increases in
SNA and hypertension. All these hypotheses need further rigor-
ous testing, but offer intriguing mechanisms by which oestrogen
acting in the brain can modulate the development of hyperten-
sion. By reviewing the role of the brain and ovarian hormones
in each of these seemingly independent risk factors, and how
they may share common mechanisms within the brain to increase
sympathetic outflow and hypertension, it is hoped that new ideas
for testing the interactions may emerge.
ACKNOWLEDGEMENTS
The author would like to acknowledge the extraordinary contribu-
tions of her long-time collaborators and colleagues Drs Baojian
Xue and Alan Kim Johnson from the University of Iowa, and Kathryn
Sandberg from Georgetown University.
FUNDING
This work has been supported by the National Institutes of Health
[HL098207] and the University of Arizona.
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