The renin–angiotensin system (RAS) plays a commanding role in the regulation of extracellular fluid homoeostasis. Tigerstadt and Bergman first identified the RAS more than two centuries ago. By the 1980s a voyage of research and discovery into the mechanisms and actions of this system led to the development of drugs that block the RAS, which have become the mainstay for the treatment of cardiovascular and renal disease. In the last 25 years new components of the RAS have come to light, including the angiotensin type 2 receptor (AT2R) and the angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1–7) [Ang(1–7)]/Mas receptor (MasR) axis. These have been shown to counter the classical actions of angiotensin II (AngII) at the predominant angiotensin type 1 receptor (AT1R). Our studies, and those of others, have demonstrated that targeting these depressor RAS pathways may be therapeutically beneficial. It is apparent that the evolution of both the pressor and depressor RAS pathways is distinct throughout life and that the depressor/pressor balance of the RAS vary between the sexes. These temporal patterns of expression suggest that therapies targeting the RAS could be optimized for discrete epochs in life.

INTRODUCTION

The renin–angiotensin system (RAS) is a key regulator of arterial pressure and water and electrolyte balance in health and disease. The main effector peptide, angiotensin II (AngII), mediates the classic actions of the RAS, including vasoconstriction, sodium retention, fibrosis and inflammation. Consequently, multiple anti-hypertensive therapies targeting the classical RAS have been developed. The classical RAS pathway begins with the cleavage of angiotensinogen by renin to form angiotensin I (AngI) (Figure 1). AngI is then converted into AngII by angiotensin-converting enzyme (ACE). AngII stimulates the angiotensin type 1 receptor (AT1R) to induce the classical actions of the RAS. Although the AT1R is the predominant angiotensin receptor expressed, AngII has ∼15-fold greater affinity for the angiotensin type 2 receptor (AT2R) than the AT1R [1]. The AT2R opposes AT1R-mediated responses by promoting vasodilation, natriuresis and anti-fibrotic and anti-inflammatory effects (Figure 1). The discovery of angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1–7) [Ang(1–7)]/Mas receptor (MasR) axis and the ability of AngII, angiotensin III (AngIII) and Ang(1–7) to stimulate the AT2R has led to the recognition of multiple depressor RAS pathways that oppose the pressor actions of AT1R stimulation (Figure 1) [2,3].

Overview of the depressor/pressor RAS

Figure 1
Overview of the depressor/pressor RAS

In the classical RAS schema, AngII is produced, via renin and ACE, to act on the angiotensin receptor subtypes, AT1R and AT2R. AngI and AngII are broken down via ACE2 to ultimately form Ang(1–7), which opposes the pressor actions of AngII. The depressor effects of Ang(1–7) are mediated by its own receptor, the MasR, and via AT2R stimulation.

Figure 1
Overview of the depressor/pressor RAS

In the classical RAS schema, AngII is produced, via renin and ACE, to act on the angiotensin receptor subtypes, AT1R and AT2R. AngI and AngII are broken down via ACE2 to ultimately form Ang(1–7), which opposes the pressor actions of AngII. The depressor effects of Ang(1–7) are mediated by its own receptor, the MasR, and via AT2R stimulation.

Targeting the pressor RAS is a mainstay of current anti-hypertensive regimens, indicating the importance of the AT1R in the pathophysiology of hypertension and cardiovascular disease (CVD). The success of ACE inhibitors (ACEis), which prevent the conversion of AngI into AngII by ACE, and angiotensin type 1 receptor blockers (ARBs), which inhibit AT1R-mediated pressor effects, has led to these drugs representing ∼55% of anti-hypertensive medications prescribed annually [4]. The efficacy of these drugs in lowering arterial pressure may, in part, be due to their ability to promote activation of the depressor RAS pathways. For example, during ARB treatment, AngII is able to stimulate the AT2R without concomitant stimulation of the AT1R, thereby promoting the depressor effects of the RAS. Whereas, administration of an ACEi prevents the formation of AngII, thereby abolishing the actions of AngII on both the AT1R and AT2R, Ang(1–7) levels may increase and elicit depressor effects via stimulation of the AT2R and the MasR [5,6]. Thus, the depressor/pressor balance of the RAS and the resultant influence of the RAS on vascular tone, pressure–natriuresis, renal haemodynamics, tubular sodium reabsorption and oxidative stress play important roles in the regulation of arterial pressure and also the progression of cardiovascular and renal diseases.

A growing body of evidence now demonstrates that the depressor/pressor balance of the RAS varies across the lifespan. Moreover, there are distinct sex differences in the depressor/pressor balance of the RAS that may underlie the sexual dimorphism of arterial pressure. The present review summarizes our current understanding of the depressor/pressor balance of the RAS during discrete stages of life and identifies pathophysiological conditions in which targeting the depressor RAS pathways may have therapeutic potential.

EARLY LIFE

Fetal and neonatal life

Expression of the AT1R and the AT2R in the vasculature and kidneys is greater during fetal life than at any other time during the lifespan [7,8]. This is underscored by the fact that during fetal life the RAS plays a key role in the regulation of arterial pressure, as well as amniotic fluid volume which is an important determinant of fetal growth and development [9]. Within the kidney, expression of the pressor RAS components (renin, ACE and AT1R) as well as the AT2R is developmentally regulated, suggesting that the RAS plays a key role in nephrogenesis [10]. Murine studies indicate that pharmacological and/or genetic disruption of renin, angiotensinogen, ACE, the AT1aR isoform or double AT1R-knockout (KO) (AT1aR and AT1bR isoforms) results in impaired renal development and function [1116]. Consistent with these findings, the use of RAS inhibitors (ARBs and ACEis) are contraindicated during pregnancy due to the high risk of fetopathy, which includes renal failure, oligohydramnios, intrauterine growth restriction, arterial hypotension and death [17]. Studies investigating genetic deficiency of ACE2, AT2R and MasR have not reported any gross morphological defects. However, these mice have enhanced pressor responses to stimulation of the RAS in later life [1822].

The transition from fetal to neonatal life requires significant cardiovascular and renal adaptations. The RAS is highly activated during this time, with plasma renin activity (PRA) and plasma AngII levels high prior to birth and the early post-partum period and declining thereafter [2325]. Postnatal ontogeny studies have demonstrated that AT1R and AT2R expression declines with renal maturation. However, renal AT2R expression decreases to a greater extent than renal AT1R expression during this period [26,27]. Moreover, the decline in renal AT2R expression is greater in males than in females [27]. The functional significance of the predominance of the AT2R during neonatal life has not been extensively studied but it opens the possibility that the AT2R may have a greater influence on renal function at this stage of life.

Recently it has been demonstrated that at 3 weeks of age in male rats, the AT2R modulates the response to AngII, blunting renal vasoconstriction [26]. Moreover, this effect was significantly attenuated with age in association with a developmental reduction in the renal AT2R/AT1R balance [26]. Conversely, Vinturache and Smith [28] found that the AT2R did not modulate the renal blood flow (RBF) response to AngII in newborn lambs. The explanation for this discrepancy may reside in the differences in timing of renal development between the species. Sheep, like humans, complete nephrogenesis some weeks prior to birth, whereas in rodents the bulk of nephrons are formed during the weaning period [29,30]. Consistent with this, it has been demonstrated that in fetal sheep, in which nephrogenesis is still active, the renal response to AngII infusion is blunted [31]. Thus, although the AT2R modulates renal function in the newborn rat, it is unlikely to play a significant role in full-term infants in which nephrogenesis is complete. However, the possibility exists that the AT2R may influence renal function in preterm infants. Certainly evidence suggests that enhanced microvascular flow is associated with augmented nitric oxide (NO) production, circulatory collapse and death in preterm infants [3234]. Moreover, male preterm babies have a reduced survival rate compared with females, again in association with greater peripheral microvascular flow [35]. The contribution of the AT2R to renal and microvascular function warrants further investigation in this setting since AT2R stimulation acts via the generation of NO and thus blockade of AT2R might be a therapeutic option to maintain peripheral vascular resistance in preterm infants.

PUBERTY

The age-related increase in arterial pressure is similar in prepubescent boys and girls [36,37]. The onset of puberty coincides with the sexual dimorphism of arterial pressure, such that from adolescence males have higher arterial pressure than females [3739]. Thus, sex hormones are thought to contribute to the sex difference in arterial pressure. Moreover, it is now well established that sex differences exist in the RAS due to differential modulation of this system by sex hormones. For example, oestrogen regulates all components of the RAS. Oestrogen increases the synthesis of angiotensinogen, while decreasing the synthesis and activity of renin and ACE. Oestrogen decreases the expression of the AT1R in target tissue, but has the opposite effect on AT2R expression [4042]. In rats, ovariectomy (OVX) decreased renal AT2R expression and oestrogen replacement increased AT2R expression [4345]. Moreover, ACE2 and MasR expression are greater in females than males [27,46]. In contrast, testosterone amplifies the expression of the AT1R and decreases AT2R expression [40,47]. Additionally, oestrogen administration to male rats has been demonstrated to enhance AT2R expression [48]. This strongly suggests differential roles for these pathways between the sexes, with the balance shifted towards the depressor RAS in females of reproductive age.

Inappropriate transition of the balance of RAS towards the depressor arm at puberty may contribute to the development of CVD in females. Polycystic ovarian syndrome (PCOS), the symptoms of which first appear at the age of menarche in association with hyperandrogenaemia, may be a condition in which targeting the depressor RAS pathways could have therapeutic benefits. In the ovary, which expresses both the AT1R and the AT2R, it has been demonstrated that the AT2R stimulates the conversion of androgen into oestrogen [49,50]. Moreover in a rodent model of PCOS, it has recently been demonstrated that AT2R stimulation was able to normalize the hyperandrogenaemia with a trend for the correction of metabolic disturbances after 1-week of treatment [51]. Thus, targeting the AT2R may have beneficial effects in ameliorating the effects of PCOS and this warrants further investigation. It is also possible that deficits in the shift in balance towards the depressor RAS pathways at puberty in females may be linked to other CVDs in women of reproductive age.

REPRODUCTIVE LIFE

Adulthood

Clinical evidence indicates a greater role for the depressor RAS pathways in women than men. This may, in part, explain why women of reproductive age are protected from cardiovascular and renal disease relative to men [52,53]. It has been demonstrated that PRA, which is the rate-limiting step in AngII synthesis, is lower in women than men [54]. Conversely, plasma Ang(1–7) levels are higher in women than men [55]. There are also reports of men and women responding to AngII and anti-hypertensive treatments differently. For example, in healthy men and women, it has been demonstrated that women have a blunted renal pressor response to AngII compared with men [56], and moreover, that AngII sensitivity is decreased to a greater extent in women than men in response to ARB treatment [57]. Furthermore, a retrospective observational study identified that the rate of survival after congestive heart failure is better for women treated with an ARB compared with an ACEi, and vice versa for men [58]. These studies suggest that the depressor RAS pathways play a greater role in the regulation of arterial pressure in women than men.

Preclinical studies have demonstrated that pressor responsiveness to AngII is attenuated in female, but not male, rodents [5964]. Remarkably, chronic infusion of AngII at a low dose paradoxically decreased arterial pressure in female Sprague–Dawley (SD) rats, at a dose that caused an increase in arterial pressure in male SD rats [44]. In subsequent studies, it was demonstrated that the depressor effect of AngII in female rats occurred via an AT2R-mediated oestrogen-dependent mechanism [44,61]. In these studies, the attenuated pressor response to AngII in females as compared with male rats was associated with an enhanced renal AT2R/AT1R balance. Moreover, it has been demonstrated that the attenuated pressor response to AngII in adult female mice is AT2R-mediated [59,65]. Collectively these findings illustrate the dual nature of AngII on the regulation of arterial pressure, and support an enhanced role for the AT2R in the regulation of arterial pressure in adult females of reproductive age.

As yet there is little evidence as to which angiotensin fragment primarily binds to the AT2R to elicit the attenuated pressor response to AngII in adult females. It is known that AngII binds with ∼15-fold greater affinity for the AT2R than the AT1R [1]. However, it has been previously demonstrated that in normotensive male rats conversion of AngII into AngIII is critical for AT2R-mediated natriuresis [6668]. Additionally, it has also been shown that Ang(1–7) evokes depressor effects in conscious male spontaneously hypertensive rats (SHRs) and Wistar–Kyoto (WKY) rats via AT2R stimulation, which in turn activates the NO/bradykinin cascade [6]. This Ang(1–7) depressor effect was abolished by the AT2R antagonist PD123319, confirming a role for the AT2R [6]. Furthermore, it has been demonstrated that the pressor response to AngII in females is dependent on the presence of ACE2, given that in female ACE2-KO mice the pressor response to AngII was enhanced [69]. Certainly, it has been demonstrated that renal ACE2 expression is 5-fold greater in adult female than in adult male mice [46]. It is likely that regional and temporal expression of the angiotensin fragments as well as ACE2 contribute to the AT2R-mediated reduction in pressor responsiveness to AngII in adult females.

Within the kidney, it has been demonstrated that the AT2R modulates the acute pressure–natriuresis relationship to a similar extent in both adult males and females [70]. Conversely, the chronic pressure–natriuresis relationship, which is generated under physiological conditions as it incorporates the neurohumoral changes that occur as part of the integrated physiological response to altered sodium intake, is modulated by the AT2R in adult female, but not male, mice [46]. There are also sex-specific effects of the AT2R within the renal vasculature. Viegas et al. [71] demonstrated that AngII-induced contraction of renal interlobar arteries was attenuated in female, but not male, mice. Moreover, AT2R blockade enhanced AngII-mediated vasoconstriction of interlobar arteries in female, but not male, mice [71]. Previously, we showed that the AT2R maintains autoregulation of RBF and glomerular filtration rate (GFR) at low renal perfusion pressures [70]. The sensitivity of the tubuloglomerular feedback mechanism, which is an important regulator of GFR, to AngII is also reduced by the presence of the AT2R in female, but not male, mice [59]. Moreover, we [72], and Kemp et al. [73], have recently demonstrated that in female rats AT2R activation using the highly selective AT2R agonist compound 21 (C21) evokes natriuresis without altering renal haemodynamic function. Thus, the AT2R appears to play a greater role in the regulation of renal function in females than males.

Within the brain, differential expression of RAS components between the sexes has also been documented [74]. Again, the differences in the RAS between males and females have been linked to the influence of the sex-hormones oestrogen and testosterone [62,74,75]. Studies have demonstrated the AT2R activation modulates sympathetic outflow and that this contributes to the control of arterial pressure, with the effect enhanced in females [76,77]. Thus, targeting the depressor RAS may impinge upon several converging pathways to influence both renal and central control of arterial pressure.

In addition to the sex-specific effects of the AT2R, accumulating evidence also indicates sex-specific effects of the ACE2/Ang(1–7)/MasR axis. Renal ACE2 and MasR gene expression are greater in female rodents than in male rodents [27,46]. Moreover, it has been reported that renal cortical levels of Ang(1–7) are greater in female SHRs than in male SHRs both basally and after exogenous AngII infusion [78]. However, MasR expression was increased in the renal cortex following AngII infusion in female SHRs only [78], suggesting that Ang(1–7) elicits its effects via the AT2R in adult males. Consistent with this notion, it has been demonstrated that Ang(1–7) elicits a vasodepressor response in adult males which is blocked by co-administration of the AT2R antagonist PD123319 [79]. Furthermore, RBF decreased significantly in female, but not male, normotensive rats when the MasR was blocked [80]. Therefore, similar to the AT2R, the MasR might also play a sex-specific role in the regulation of arterial pressure. Collectively, these data demonstrate an enhanced role for the regulation of renal function and arterial pressure by the depressor RAS pathways in females.

RAS blockade can indirectly ameliorate fibrosis by both limiting hypertensive damage, and directly by inhibiting the AngII/transforming growth factor (TGF)-β1 axis. However, the current best anti-fibrotic therapies, ARBs and ACEis, only delay progression by a matter of months, and can be associated with side effects [81,82]. Hence, novel strategies that target collagen turnover and organization and limit fibrosis will provide significant therapeutic benefits. Currently there is substantial evidence to indicate that pharmacological AT2R stimulation offers end-organ protection (heart and kidney) in the setting of CVD and neuroprotection following stroke [83]. Conversely, although there is a consensus in the literature that direct AT2R stimulation has minimal or negligible effects on arterial pressure [8487], these studies were universally performed in males. Taking into consideration that major sex differences exist in the mechanisms that regulate arterial pressure, these findings in males may not necessarily translate directly to females. Indeed, Kemp et al. [73] have recently demonstrated that intrarenal AT2R activation lowers arterial pressure during AngII-induced hypertension in adult female SD rats without concomitant AT1R blockade. Thus, chronic direct stimulation of the AT2R alone, or in combination with other anti-hypertensive therapies, may prove beneficial in females. Indeed, novel compounds to stimulate both the AT2R and MasR are being developed [88].

Pregnancy

Pregnancy is associated with significant cardiovascular and renal adaptations that facilitate the metabolic demands of the mother and the growing fetus. It has been demonstrated that normotensive pregnant women and gravid animal models are less sensitive to the pressor effects of AngII [89,90], that Ang(1–7) plasma levels are increased [90] and that the AT2R/AT1R balance rises during normotensive pregnancy [90]. Thus, compared with non-pregnant females, the depressor/pressor balance of the RAS is shifted further towards the depressor RAS pathways during pregnancy.

Pre-eclampsia, a pregnancy-induced hypertensive disorder characterized by enhanced pressor responsiveness to AngII, is associated with lower plasma Ang(1–7) levels, polymorphism in the AT2R gene and a reduction in the AT2R/AT1R balance [9193]. Recently, using the gold-standard technology of radio-telemetry, we demonstrated for the first time the full impact of the AT2R on arterial pressure throughout gestation and during the post-partum period [94]. These powerful striking data show the complete time-course of arterial pressure across gestation. It was observed that the normal decline in arterial pressure during gestation is mediated by the AT2R, since the fall in arterial pressure during gestation was abolished in AT2R-deficient mice, confirming previous reports [9597]. Moreover, AT2R-deficient mice had greater arterial pressure during late gestation, which was associated with a shift in the pressure–natriuresis relationship and an increase in pro-inflammatory T helper type 1 cells within the kidney [94]. Similarly, it has also been shown that ACE2-KO mice have higher arterial pressure during late gestation than WT mice, which was suggested to be due to altered renal function [98]. Additionally, accumulating evidence suggests that the ACE2/Ang(1–7)/MasR axis plays a key role in the uteroplacental unit [99101]. These findings support a role for the depressor RAS pathways in mediating the normal cardiovascular and renal adaptations to pregnancy.

Although previous studies provide evidence that the depressor RAS contributes to arterial pressure regulation during pregnancy, they have not investigated the underlying mechanisms by which the AT2R and ACE2 elicits this effect. Within the kidney, AT2R, ACE2 and Ang(1–7) levels increase during pregnancy [98,102]. This requires a functional NO system [103], which may act via the depressor RAS, since, as described above, the AT2R and MasR produce their effects via the generation of NO [104,105]. Indeed, urinary nitrate excretion as well as serum, renal and uterine NO production is increased during pregnancy [106]. Thus, enhanced depressor RAS pathways may facilitate the increase in NO production during pregnancy. Hence, more studies are needed to establish the exact nature of the contribution of the depressor RAS pathways to the regulation of arterial pressure during pregnancy, to delineate the mechanisms by which the depressor RAS elicits its arterial pressure lowering effects during pregnancy. Targeting deficits in the depressor RAS pathways may provide protect against pregnancy-induced hypertension, conferring benefit for both the mother and fetus.

Clinical translation of this postulate to human pregnancy will be difficult given that the use of ACEis and ARBs are contraindicated during pregnancy [107]. However, in preclinical models, inhibition or deficiency of components of the depressor RAS pathways (AT2R, MasR and ACE2) has not been reported to cause major defects in fetal growth and development [1822]. Although direct stimulation of AT2R during pregnancy has not been previously examined in vivo, studies in pregnant rats have demonstrated an enhanced contribution of the AT2R to vascular tone in isolated vessels [108]. Thus, given the real need for therapeutic options to treat hypertensive pregnancies, the possibilities for AT2R and/or MasR stimulation should be further investigated.

REPRODUCTIVE SENESCENCE

Aging

Aging in both men and women is characterized by increasing arterial pressure [109111]. In fact, the age-related increase in arterial pressure is greater in women post-menopause such that by approximately 80 years of age, arterial pressure matches or exceeds that measured in men [111]. Moreover, older post-menopausal (70–79 years of age) women are less likely to have their arterial pressure under control using anti-hypertensive medication than younger post-menopausal (50–69 years of age) women [109,112]. Given that the mechanisms underlying the increase in arterial pressure in post-menopausal women are still being elucidated [113], the best therapeutic options for the treatment of post-menopausal hypertension remain unclear.

Similar to humans, arterial pressure increases following reproductive senescence in aging female rodents to match that measured in males [114,115]. Moreover, in both humans and rodents, this increase in arterial pressure is linked with a decrease in the oestrogen/testosterone ratio and an increase in PRA [115118], suggesting that a shift in depressor/pressor balance of the RAS may contribute to the higher arterial pressure observed following reproductive senescence in females (Table 1). In this regard, it has been demonstrated that reproductively senescent female mice have reduced vascular and renal AT2R expression than their adult counterparts [46,65,119]. Furthermore, renal AT1R expression is greater in aged reproductively senescent female mice, such that there is a reduction in renal AT2R/AT1R balance as compared with adult female mice [46,65]. Conversely, renal ACE2 and MasR gene expression are similar in adult and aged reproductively senescent female mice [46,65].

Table 1
Age-related changes in expression of components of the RAS in males and females
Aged compared with adult
RAS componentMaleFemale
Plasma renin Humans Humans 
 ↑ [123↑ [118,123,124
 Rats Rats 
 ↓ [115↑ [115,125
Angiotensinogen  Humans 
  ↓ [118,124,126,127
  Rats 
  ↑ plasma [125
  ← → renal [125
ACE  Humans 
  ↑ plasma [118,130
 Rats Rats 
 ↑ renal [128,129← → renal [125
 ↑ cardiac [128,129 
AngII  Humans 
  ← → plasma [124
 Rats  
 ↓ renal [131 
AT1Rats Rats 
 ↑ renal [128,129↓ and ↑ renal [125,132
 ↑ cardiac [128,129 
 ← → aorta [79 
 Mice Mice 
 ← → renal [46,65↑ renal [46,65
AT2Rats Rats 
 ↓ renal [128,129← → renal [125
 ← → cardiac [128,129 
 ↑ aorta [79 
 Mice Mice 
 ← → renal [46,65↓ renal [46,65
ACE2 Rats  
 ↓ renal [128 
 ↑ aorta [79 
 Mice Mice 
 ← → renal [46,65← → renal [46,65
Ang(1–7) Unknown Unknown 
MasR Rats  
 ↑ aorta [79 
 Mice Mice 
 ← → renal [46,65← → renal [46,65
Aged compared with adult
RAS componentMaleFemale
Plasma renin Humans Humans 
 ↑ [123↑ [118,123,124
 Rats Rats 
 ↓ [115↑ [115,125
Angiotensinogen  Humans 
  ↓ [118,124,126,127
  Rats 
  ↑ plasma [125
  ← → renal [125
ACE  Humans 
  ↑ plasma [118,130
 Rats Rats 
 ↑ renal [128,129← → renal [125
 ↑ cardiac [128,129 
AngII  Humans 
  ← → plasma [124
 Rats  
 ↓ renal [131 
AT1Rats Rats 
 ↑ renal [128,129↓ and ↑ renal [125,132
 ↑ cardiac [128,129 
 ← → aorta [79 
 Mice Mice 
 ← → renal [46,65↑ renal [46,65
AT2Rats Rats 
 ↓ renal [128,129← → renal [125
 ← → cardiac [128,129 
 ↑ aorta [79 
 Mice Mice 
 ← → renal [46,65↓ renal [46,65
ACE2 Rats  
 ↓ renal [128 
 ↑ aorta [79 
 Mice Mice 
 ← → renal [46,65← → renal [46,65
Ang(1–7) Unknown Unknown 
MasR Rats  
 ↑ aorta [79 
 Mice Mice 
 ← → renal [46,65← → renal [46,65

Our recent work indicates that the contribution of the AT2R to the regulation of arterial pressure is reduced in aging females in association with the altered hormonal status. We observed that, compared with adult female WT mice, the chronic pressure–natriuresis relationship was shifted rightwards in aged reproductively senescent WT mice similar to that observed in female AT2R-KO mice [46]. As such, aged reproductively senescent females excrete the same amount of sodium as adult females, but at a higher arterial pressure. Moreover, these aged reproductively senescent females have enhanced pressor responsiveness to AngII, with the increase in arterial pressure similar to that observed in female AT2R-KO mice [65]. Perhaps one of our most striking findings was that in aged reproductively senescent female mice, renal AT2R expression was increased in response to AngII-induced hypertension [65]. Moreover, ACE2 expression was increased 2-fold following AngII-induced hypertension, indicating an increase in the conversion of AngII into Ang(1–7) [65]. However, this did not translate into arterial pressure-lowering effects, suggesting that deficits exist in the signalling pathways for the AT2R, and potentially the MasR, in aged reproductively senescent females. Thus, loss of the protective effects of AT2R activation may contribute to age-related differences in arterial pressure and disease protection particularly in terms of cardiovascular and renal disease. Whether the protective effects of the AT2R and/or the MasR can be restored in aged reproductively senescent females remains to be seen.

In males, sensitivity to AngII increases with aging [120,121]. Depending on the tissue, AT1R expression is unchanged or increases with advancing age. For example, it has been demonstrated that cardiac AT1R expression is increased in aging male WKY rats [122]. Moreover, in aging WKY male rats, components of the depressor RAS (ACE2, AT2R, MasR) are in increased in the thoracic aorta [79]. Conversely, within the thoracic aorta, femoral artery and kidneys, expression of components of the depressor RAS are similar in adult and aged male rodents [46,79,119]. Thus, in aged males the depressor/pressor balance of the RAS is still tipped towards the pressor pathway (Table 1). This may contribute to the greater age-dependent loss of renal function observed in males [121]. Indeed, we observed that chronic pressure–natriuresis relationship of male mice is shifted further rightwards with advancing age as compared with age-matched females [46]. Thus, it is likely that targeting the protective depressor RAS pathways may protect against the age-related increases in arterial pressure and the progression of renal dysfunction, not only in females, but also in males.

SUMMARY

The balance between the depressor and pressor RAS pathways and their roles in the control of vascular tone and cardiovascular remodelling are complex and are yet to be fully elucidated. However, there is potential for the application of therapies targeting the AT2R and/or the MasR at different epochs in life. Inhibition of the AT2R may help to maintain arterial pressure and renal function in the newborn. The actions of the depressor RAS pathways are amplified in adult females conferring benefit for disease progression in many instances, particularly for conditions that are particular to women (PCOS, pregnancy). Moreover, in aged reproductively senescent females, the protective effects of AT2R activation on the regulation of arterial pressure are lost. Consequently, an AT2R agonist may represent a novel approach in the management of hypertension and CVD, particularly in aged females, warranting further studies into the chronic and sex-dependent effects of AT2R activation. Understanding how the depressor RAS pathways contribute to the regulation of renal function and hence arterial pressure in neonatal, adult and aged females and how the protective effects of the depressor RAS pathways are lost could be used to lower morbidity and mortality in males, and maintain protection in females.

FUNDING

This work was supported by the National Health and Medical Research Council of Australia [grant number 1041844 (to K.M.D.)].

Abbreviations

     
  • ACE

    angiotensin-converting enzyme

  •  
  • ACE2

    angiotensin-converting enzyme 2

  •  
  • ACEi

    angiotensin-converting enzyme inhibitor

  •  
  • AngI

    angiotensin I

  •  
  • AngII

    angiotensin II

  •  
  • AngIII

    angiotensin III

  •  
  • Ang(1–7)

    angiotensin-(1–7)

  •  
  • ARB

    angiotensin type 1 receptor blocker

  •  
  • AT1R

    angiotensin type 1 receptor

  •  
  • AT2R

    angiotensin type 2 receptor

  •  
  • C21

    compound 21

  •  
  • CVD

    cardiovascular disease

  •  
  • GFR

    glomerular filtration rate

  •  
  • KO

    knockout

  •  
  • MasR

    Mas receptor

  •  
  • PCOS

    polycystic ovarian syndrome

  •  
  • PRA

    plasma renin activity

  •  
  • RAS

    renin–angiotensin system

  •  
  • RBF

    renal blood flow

  •  
  • SD

    Sprague–Dawley

  •  
  • SHR

    spontaneously hypertensive rat

  •  
  • WKY

    Wistar–Kyoto

References

References
1
Bosnyak
 
S.
Jones
 
E.S.
Christopoulos
 
A.
Aguilar
 
M.I.
Thomas
 
W.G.
Widdop
 
R.E.
 
Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors
Clin. Sci.
2011
, vol. 
121
 (pg. 
297
-
303
)
[PubMed]
2
Ingelfinger
 
J.R.
Jung
 
F.
Diamant
 
D.
Haveran
 
L.
Lee
 
E.
Brem
 
A.
Tang
 
S.S.
 
Rat proximal tubule cell line transformed with origin-defective SV40 DNA: autocrine Ang II feedback
Am. J. Physiol.
1999
, vol. 
276
 (pg. 
F218
-
F227
)
[PubMed]
3
Donoghue
 
M.
Hsieh
 
F.
Baronas
 
E.
Godbout
 
K.
Gosselin
 
M.
Stagliano
 
N.
Donovan
 
M.
Woolf
 
B.
Robison
 
K.
Jeyaseelan
 
R.
, et al 
A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin
Circ. Res.
2000
, vol. 
87
 (pg. 
e1
-
e9
)
[PubMed]
4
Ma
 
J.
Lee
 
K.V.
Stafford
 
R.S.
 
Changes in antihypertensive prescribing during US outpatient visits for uncomplicated hypertension between 1993 and 2004
Hypertension
2006
, vol. 
48
 (pg. 
846
-
852
)
[PubMed]
5
Castro
 
C.H.
Santos
 
R.A.
Ferreira
 
A.J.
Bader
 
M.
Alenina
 
N.
Almeida
 
A.P.
 
Evidence for a functional interaction of the angiotensin-(1–7) receptor Mas with AT1 and AT2 receptors in the mouse heart
Hypertension
2005
, vol. 
46
 (pg. 
937
-
942
)
[PubMed]
6
Walters
 
P.E.
Gaspari
 
T.A.
Widdop
 
R.E.
 
Angiotensin-(1–7) acts as a vasodepressor agent via angiotensin II type 2 receptors in conscious rats
Hypertension
2005
, vol. 
45
 (pg. 
960
-
966
)
[PubMed]
7
Fogo
 
A.
Ichikawa
 
I.
 
Renin angiotensin system in development of mice and men
Am. J. Pathol.
1996
, vol. 
149
 (pg. 
1797
-
1801
)
[PubMed]
8
Vinturache
 
A.E.
Smith
 
F.G.
 
Angiotensin type 1 and type 2 receptors during ontogeny: cardiovascular and renal effects
Vascul. Pharmacol.
2014
, vol. 
63
 (pg. 
145
-
154
)
[PubMed]
9
Lumbers
 
E.R.
 
Functions of the renin angiotensin system during development
Clin. Exp. Pharmacol. Physiol.
1995
, vol. 
22
 (pg. 
499
-
505
)
[PubMed]
10
Guron
 
G.
Friberg
 
P.
 
An intact renin angiotensin system is a prerequisite for normal renal development
J. Hypertens.
2000
, vol. 
18
 (pg. 
123
-
137
)
[PubMed]
11
Davisson
 
R.L.
Kim
 
H.S.
Krege
 
J.H.
Lager
 
D.J.
Smithies
 
O.
Sigmund
 
C.D.
 
Complementation of reduced survival, hypotension, and renal abnormalities in angiotensinogen-deficient mice by the human renin and human angiotensinogen genes
J. Clin. Invest.
1997
, vol. 
99
 (pg. 
1258
-
1264
)
[PubMed]
12
Esther
 
C.R.
Howard
 
T.E.
Marino
 
E.M.
Goddard
 
J.M.
Capecchi
 
M.R.
Bernstein
 
K.E.
 
Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male fertility
Lab. Invest.
1996
, vol. 
74
 (pg. 
953
-
965
)
[PubMed]
13
Niimura
 
F.
Labosky
 
P.A.
Kakuchi
 
J.
Okubo
 
S.
Yoshida
 
H.
Oikawa
 
T.
Ichiki
 
T.
Naftilan
 
A.J.
Fogo
 
A.
Inagami
 
T.
, et al 
Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation
J. Clin. Invest.
1995
, vol. 
96
 (pg. 
2947
-
2954
)
[PubMed]
14
Kim
 
H.S.
Krege
 
J.H.
Kluckman
 
K.D.
Hagaman
 
J.R.
Hodgin
 
J.B.
Best
 
C.F.
Jennette
 
J.C.
Coffman
 
T.M.
Maeda
 
N.
Smithies
 
O.
 
Genetic control of blood pressure and the angiotensinogen locus
Proc. Natl. Acad. Sci. U.S.A.
1995
, vol. 
92
 (pg. 
2735
-
2739
)
[PubMed]
15
Oliverio
 
M.I.
Madsen
 
K.
Best
 
C.F.
Ito
 
M.
Maeda
 
N.
Smithies
 
O.
Coffman
 
T.M.
 
Renal growth and development in mice lacking AT1A receptors for angiotensin II
Am. J. Physiol.
1998
, vol. 
274
 (pg. 
F43
-
F50
)
[PubMed]
16
Oliverio
 
M.I.
Kim
 
H.S.
Ito
 
M.
Le
 
T.
Audoly
 
L.
Best
 
C.F.
Hiller
 
S.
Kluckman
 
K.
Maeda
 
N.
Smithies
 
O.
, et al 
Reduced growth, abnormal kidney structure, and type 2 (AT2) angiotensin receptor-mediated blood pressure regulation in mice lacking both AT1A and AT1B receptors for angiotensin II
Proc. Natl. Acad. Sci. U.S.A.
1998
, vol. 
95
 (pg. 
15496
-
15501
)
[PubMed]
17
Bullo
 
M.
Tschumi
 
S.
Bucher
 
B.S.
Bianchetti
 
M.G.
Simonetti
 
G.D.
 
Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists: a systematic review
Hypertension
2012
, vol. 
60
 (pg. 
444
-
450
)
[PubMed]
18
Hein
 
L.
Barsh
 
G.S.
Pratt
 
R.E.
Dzau
 
V.J.
Kobilka
 
B.K.
 
Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor in mice
Nature
1995
, vol. 
377
 (pg. 
744
-
747
)
[PubMed]
19
Ichiki
 
T.
Labosky
 
P.A.
Shiota
 
C.
Okuyama
 
S.
Imagawa
 
Y.
Fogo
 
A.
Niimura
 
F.
Ichikawa
 
I.
Hogan
 
B.L.
Inagami
 
T.
 
Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor
Nature
1995
, vol. 
377
 (pg. 
748
-
750
)
[PubMed]
20
Gurley
 
S.B.
Allred
 
A.
Le
 
T.H.
Griffiths
 
R.
Mao
 
L.
Philip
 
N.
Haystead
 
T.A.
Donoghue
 
M.
Breitbart
 
R.E.
Acton
 
S.L.
, et al 
Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice
J. Clin. Invest.
2006
, vol. 
116
 (pg. 
2218
-
2225
)
[PubMed]
21
Crackower
 
M.A.
Sarao
 
R.
Oudit
 
G.Y.
Yagil
 
C.
Kozieradzki
 
I.
Scanga
 
S.E.
Oliveira-dos-Santos
 
A.J.
da Costa
 
J.
Zhang
 
L.
Pei
 
Y.
, et al 
Angiotensin-converting enzyme 2 is an essential regulator of heart function
Nature
2002
, vol. 
417
 (pg. 
822
-
828
)
[PubMed]
22
Alenina
 
N.
Xu
 
P.
Rentzsch
 
B.
Patkin
 
E.L.
Bader
 
M.
 
Genetically altered animal models for Mas and angiotensin-(1–7)
Exp. Physiol.
2008
, vol. 
93
 (pg. 
528
-
537
)
[PubMed]
23
Gomez
 
R.A.
Tufro-McReddie
 
A.
Everett
 
A.D.
Pentz
 
E.S.
 
Ontogeny of renin and AT1 receptor in the rat
Pediatr. Nephrol.
1993
, vol. 
7
 (pg. 
635
-
638
)
[PubMed]
24
Monument
 
M.J.
Smith
 
F.G.
 
Age-dependent effects of captopril on the arterial baroreflex control of heart rate in conscious lambs
Exp. Physiol.
2003
, vol. 
88
 (pg. 
761
-
768
)
[PubMed]
25
Chappellaz
 
M.L.
Smith
 
F.G.
 
Systemic and renal hemodynamic effects of the AT1 receptor antagonist, ZD7155, and the AT2 receptor antagonist, PD123319, in conscious lambs
Pflugers Arch.
2007
, vol. 
453
 (pg. 
477
-
486
)
[PubMed]
26
Brown
 
R.D.
Hilliard
 
L.M.
Mirabito
 
K.M.
Firth
 
L.C.
Moritz
 
K.M.
Evans
 
R.G.
Denton
 
K.M.
 
Reduced sensitivity of the renal vasculature to angiotensin II in young rats, the role of the angiotensin type 2 receptor
Pediatr. Res.
2014
, vol. 
76
 (pg. 
448
-
452
)
[PubMed]
27
Sampson
 
A.K.
Moritz
 
K.M.
Denton
 
K.M.
 
Postnatal ontogeny of angiotensin receptors and ACE2 in male and female rats
Gend. Med.
2012
, vol. 
9
 (pg. 
21
-
32
)
[PubMed]
28
Vinturache
 
A.E.
Smith
 
F.G.
 
Do angiotensin type 2 receptors modulate haemodynamic effects of type 1 receptors in conscious newborn lambs?
J. Renin. Angiotensin Aldosterone Syst.
2014
, vol. 
15
 (pg. 
450
-
457
)
[PubMed]
29
Moritz
 
K.M.
Wintour
 
E.M.
 
Functional development of the meso- and metanephros
Pediatr. Nephrol.
1999
, vol. 
13
 (pg. 
171
-
178
)
[PubMed]
30
Merlet-Benichou
 
C.
Gilbert
 
T.
Muffat-Joly
 
M.
Lelievre-Pegorier
 
M.
Leroy
 
B.
 
Intrauterine growth retardation leads to a permanent nephron deficit in the rat
Pediatr. Nephrol.
1994
, vol. 
8
 (pg. 
175
-
180
)
[PubMed]
31
Stevenson
 
K.M.
Lumbers
 
E.R.
 
Effects of angiotensin II in fetal sheep and modification of its actions by indomethacin
J. Physiol.
1995
, vol. 
487
 (pg. 
147
-
158
)
[PubMed]
32
Schwepcke
 
A.
Weber
 
F.D.
Mormanova
 
Z.
Cepissak
 
B.
Genzel-Boroviczeny
 
O.
 
Microcirculatory mechanisms in postnatal hypotension affecting premature infants
Pediatr. Res.
2013
, vol. 
74
 (pg. 
186
-
190
)
[PubMed]
33
Ishiguro
 
A.
Sekine
 
T.
Suzuki
 
K.
Kurishima
 
C.
Ezaki
 
S.
Kunikata
 
T.
Sobajima
 
H.
Tamura
 
M.
 
Changes in skin and subcutaneous perfusion in very low birth weight infants during the transitional period
Neonatology
2011
, vol. 
100
 (pg. 
162
-
168
)
[PubMed]
34
Stark
 
M.J.
Clifton
 
V.L.
Wright
 
I.M.
 
Microvascular flow, clinical illness severity and cardiovascular function in the preterm infant
Arch. Dis. Child Fetal. Neonatal Ed.
2008
, vol. 
93
 (pg. 
F271
-
F274
)
[PubMed]
35
Stark
 
M.J.
Clifton
 
V.L.
Wright
 
I.M.
 
Sex-specific differences in peripheral microvascular blood flow in preterm infants
Pediatr. Res.
2008
, vol. 
63
 (pg. 
415
-
419
)
[PubMed]
36
Lee
 
M.H.
Kang
 
D.R.
Kim
 
H.C.
Ahn
 
S.V.
Khaw
 
K.T.
Suh
 
I.
 
A 24-year follow-up study of blood pressure tracking from childhood to adulthood in Korea, the Kangwha Study
Yonsei Med. J.
2014
, vol. 
55
 (pg. 
360
-
366
)
[PubMed]
37
Bachmann
 
H.
Horacek
 
U.
Leowsky
 
M.
Hirche
 
H.
 
Blood pressure in children and adolescents aged 4 to 18. Correlation of blood pressure values with age, sex, body height, body weight and skinfold thickness (Essen Blood Pressure Study)
Monatsschr. Kinderheilkd.
1987
, vol. 
135
 (pg. 
128
-
134
)
[PubMed]
38
Kotchen
 
J.M.
McKean
 
H.E.
Kotchen
 
T.A.
 
Blood pressure trends with aging
Hypertension
1982
, vol. 
4
 (pg. 
III128
-
III134
)
[PubMed]
39
Hilliard
 
L.M.
Sampson
 
A.K.
Brown
 
R.D.
Denton
 
K.M.
 
The “his and hers” of the renin angiotensin system
Curr. Hypertens. Rep.
2013
, vol. 
15
 (pg. 
71
-
79
)
[PubMed]
40
Rogers
 
J.L.
Mitchell
 
A.R.
Maric
 
C.
Sandberg
 
K.
Myers
 
A.
Mulroney
 
S.E.
 
Effect of sex hormones on renal estrogen and angiotensin type 1 receptors in female and male rats
Am. J. Physiol. Regul. Integr. Comp. Physiol.
2007
, vol. 
292
 (pg. 
R794
-
R799
)
[PubMed]
41
Armando
 
I.
Jezova
 
M.
Juorio
 
A.V.
Terron
 
J.A.
Falcon-Neri
 
A.
Semino-Mora
 
C.
Imboden
 
H.
Saavedra
 
J.M.
 
Estrogen upregulates renal angiotensin II AT2 receptors
Am. J. Physiol. Renal Physiol.
2002
, vol. 
283
 (pg. 
F934
-
F943
)
[PubMed]
42
Baiardi
 
G.
Macova
 
M.
Armando
 
I.
Ando
 
H.
Tyurmin
 
D.
Saavedra
 
J.M.
 
Estrogen upregulates renal angiotensin II AT1 and AT2 receptors in the rat
Regul. Pept.
2005
, vol. 
124
 (pg. 
7
-
17
)
[PubMed]
43
Nickenig
 
G.
Baumer
 
A.T.
Grohe
 
C.
Kahlert
 
S.
Strehlow
 
K.
Rosenkranz
 
S.
Stablein
 
A.
Beckers
 
F.
Smits
 
J.F.
Daemen
 
M.J.
, et al 
Estrogen modulates AT1 receptor gene expression in vitro and in vivo
Circulation
1998
, vol. 
97
 (pg. 
2197
-
2201
)
[PubMed]
44
Sampson
 
A.K.
Hilliard
 
L.M.
Moritz
 
K.M.
Thomas
 
M.C.
Tikellis
 
C.
Widdop
 
R.E.
Denton
 
K.M.
 
The arterial depressor response to chronic low-dose angiotensin II infusion in female rats is estrogen dependent
Am. J. Physiol. Regul. Integr. Comp. Physiol.
2012
, vol. 
302
 (pg. 
R159
-
R165
)
[PubMed]
45
Macova
 
M.
Armando
 
I.
Zhou
 
J.
Baiardi
 
G.
Tyurmin
 
D.
Larrayoz-Roldan
 
I.M.
Saavedra
 
J.M.
 
Estrogen reduces aldosterone, upregulates adrenal angiotensin II AT2 receptors and normalizes adrenomedullary Fra-2 in ovariectomized rats
Neuroendocrinology
2008
, vol. 
88
 (pg. 
276
-
286
)
[PubMed]
46
Mirabito
 
K.M.
Hilliard
 
L.M.
Kett
 
M.M.
Brown
 
R.D.
Booth
 
S.C.
Widdop
 
R.E.
Moritz
 
K.M.
Evans
 
R.G.
Denton
 
K.M.
 
Sex- and age-related differences in the chronic pressure-natriuresis relationship, role of the angiotensin type 2 receptor
Am. J. Physiol. Renal Physiol.
2014
, vol. 
307
 (pg. 
F901
-
F907
)
[PubMed]
47
Silva-Antonialli
 
M.M.
Tostes
 
R.C.
Fernandes
 
L.
Fior-Chadi
 
D.R.
Akamine
 
E.H.
Carvalho
 
M.H.
Fortes
 
Z.B.
Nigro
 
D.
 
A lower ratio of AT1/AT2 receptors of angiotensin II is found in female than in male spontaneously hypertensive rats
Cardiovasc. Res.
2004
, vol. 
62
 (pg. 
587
-
593
)
[PubMed]
48
Reckelhoff
 
J.F.
Zhang
 
H.
Granger
 
J.P.
 
Testosterone exacerbates hypertension and reduces pressure-natriuresis in male spontaneously hypertensive rats
Hypertension
1998
, vol. 
31
 (pg. 
435
-
439
)
[PubMed]
49
Pucell
 
A.G.
Hodges
 
J.C.
Sen
 
I.
Bumpus
 
F.M.
Husain
 
A.
 
Biochemical properties of the ovarian granulosa cell type 2-angiotensin II receptor
Endocrinology
1991
, vol. 
128
 (pg. 
1947
-
1959
)
[PubMed]
50
Yoshimura
 
Y.
Karube
 
M.
Aoki
 
H.
Oda
 
T.
Koyama
 
N.
Nagai
 
A.
Akimoto
 
Y.
Hirano
 
H.
Nakamura
 
Y.
 
Angiotensin II induces ovulation and oocyte maturation in rabbit ovaries via the AT2 receptor subtype
Endocrinology
1996
, vol. 
137
 (pg. 
1204
-
1211
)
[PubMed]
51
Leblanc
 
S.
Battista
 
M.C.
Noll
 
C.
Hallberg
 
A.
Gallo-Payet
 
N.
Carpentier
 
A.C.
Vine
 
D.F.
Baillargeon
 
J.P.
 
Angiotensin II type 2 receptor stimulation improves fatty acid ovarian uptake and hyperandrogenemia in an obese rat model of polycystic ovary syndrome
Endocrinology
2014
, vol. 
155
 (pg. 
3684
-
3693
)
[PubMed]
52
Pilote
 
L.
Dasgupta
 
K.
Guru
 
V.
Humphries
 
K.H.
McGrath
 
J.
Norris
 
C.
Rabi
 
D.
Tremblay
 
J.
Alamian
 
A.
Barnett
 
T.
, et al 
A comprehensive view of sex-specific issues related to cardiovascular disease
CMAJ
2007
, vol. 
176
 (pg. 
S1
-
S44
)
[PubMed]
53
Silbiger
 
S.
Neugarten
 
J.
 
Gender and human chronic renal disease
Gend. Med.
2008
, vol. 
5
 
Suppl. A
(pg. 
S3
-
S10
)
[PubMed]
54
Danser
 
A.H.
Derkx
 
F.H.
Schalekamp
 
M.A.
Hense
 
H.W.
Riegger
 
G.A.
Schunkert
 
H.
 
Determinants of interindividual variation of renin and prorenin concentrations, evidence for a sexual dimorphism of (pro)renin levels in humans
J. Hypertens.
1998
, vol. 
16
 (pg. 
853
-
862
)
[PubMed]
55
Sullivan
 
J.C.
Rodriguez-Miguelez
 
P.
Zimmerman
 
M.A.
Harris
 
R.A.
 
Differences in angiotensin (1–7) between men and women
Am. J. Physiol. Heart Circ. Physiol.
2015
, vol. 
308
 (pg. 
H1171
-
H1176
)
[PubMed]
56
Miller
 
J.A.
Anacta
 
L.A.
Cattran
 
D.C.
 
Impact of gender on the renal response to angiotensin II
Kidney Int.
1999
, vol. 
55
 (pg. 
278
-
285
)
[PubMed]
57
Miller
 
J.A.
Cherney
 
D.Z.
Duncan
 
J.A.
Lai
 
V.
Burns
 
K.D.
Kennedy
 
C.R.
Zimpelmann
 
J.
Gao
 
W.
Cattran
 
D.C.
Scholey
 
J.W.
 
Gender differences in the renal response to renin angiotensin system blockade
J. Am. Soc. Nephrol.
2006
, vol. 
17
 (pg. 
2554
-
2560
)
[PubMed]
58
Hudson
 
M.
Rahme
 
E.
Behlouli
 
H.
Sheppard
 
R.
Pilote
 
L.
 
Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure–a population study
Eur. J. Heart Fail.
2007
, vol. 
9
 (pg. 
602
-
609
)
[PubMed]
59
Brown
 
R.D.
Hilliard
 
L.M.
Head
 
G.A.
Jones
 
E.S.
Widdop
 
R.E.
Denton
 
K.M.
 
Sex differences in the pressor and tubuloglomerular feedback response to angiotensin II
Hypertension
2012
, vol. 
59
 (pg. 
129
-
135
)
[PubMed]
60
Sampson
 
A.K.
Widdop
 
R.E.
Denton
 
K.M.
 
Sex-differences in circadian blood pressure variations in response to chronic angiotensin II infusion in rats
Clin. Exp. Pharmacol. Physiol.
2008
, vol. 
35
 (pg. 
391
-
395
)
[PubMed]
61
Sampson
 
A.K.
Moritz
 
K.M.
Jones
 
E.S.
Flower
 
R.L.
Widdop
 
R.E.
Denton
 
K.M.
 
Enhanced angiotensin II type 2 receptor mechanisms mediate decreases in arterial pressure attributable to chronic low-dose angiotensin II in female rats
Hypertension
2008
, vol. 
52
 (pg. 
666
-
671
)
[PubMed]
62
Xue
 
B.
Pamidimukkala
 
J.
Hay
 
M.
 
Sex differences in the development of angiotensin II-induced hypertension in conscious mice
Am. J. Physiol. Heart Circ. Physiol.
2005
, vol. 
288
 (pg. 
H2177
-
H2184
)
[PubMed]
63
Tatchum-Talom
 
R.
Eyster
 
K.M.
Martin
 
D.S.
 
Sexual dimorphism in angiotensin II-induced hypertension and vascular alterations
Can. J. Physiol. Pharmacol.
2005
, vol. 
83
 (pg. 
413
-
422
)
[PubMed]
64
Schneider
 
M.P.
Wach
 
P.F.
Durley
 
M.K.
Pollock
 
J.S.
Pollock
 
D.M.
 
Sex differences in acute ANG II-mediated hemodynamic responses in mice
Am. J. Physiol. Regul. Integr. Comp. Physiol.
2010
, vol. 
299
 (pg. 
R899
-
R906
)
[PubMed]
65
Mirabito
 
K.M.
Hilliard
 
L.M.
Head
 
G.A.
Widdop
 
R.E.
Denton
 
K.M.
 
Pressor responsiveness to angiotensin II in female mice is enhanced with age, role of the angiotensin type 2 receptor
Biol. Sex Differ.
2014
, vol. 
5
 pg. 
13
 
[PubMed]
66
Padia
 
S.H.
Kemp
 
B.A.
Howell
 
N.L.
Fournie-Zaluski
 
M.C.
Roques
 
B.P.
Carey
 
R.M.
 
Conversion of renal angiotensin II to angiotensin III is critical for AT2 receptor-mediated natriuresis in rats
Hypertension
2008
, vol. 
51
 (pg. 
460
-
465
)
[PubMed]
67
Padia
 
S.H.
Kemp
 
B.A.
Howell
 
N.L.
Gildea
 
J.J.
Keller
 
S.R.
Carey
 
R.M.
 
Intrarenal angiotensin III infusion induces natriuresis and angiotensin type 2 receptor translocation in Wistar-Kyoto but not in spontaneously hypertensive rats
Hypertension
2009
, vol. 
53
 (pg. 
338
-
343
)
[PubMed]
68
Padia
 
S.H.
Kemp
 
B.A.
Howell
 
N.L.
Siragy
 
H.M.
Fournie-Zaluski
 
M.C.
Roques
 
B.P.
Carey
 
R.M.
 
Intrarenal aminopeptidase N inhibition augments natriuretic responses to angiotensin III in angiotensin type 1 receptor-blocked rats
Hypertension
2007
, vol. 
49
 (pg. 
625
-
630
)
[PubMed]
69
Liu
 
J.
Ji
 
H.
Zheng
 
W.
Wu
 
X.
Zhu
 
J.J.
Arnold
 
A.P.
Sandberg
 
K.
 
Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17beta-oestradiol-dependent and sex chromosome-independent
Biol. Sex Differ.
2010
, vol. 
1
 pg. 
6
 
[PubMed]
70
Hilliard
 
L.M.
Nematbakhsh
 
M.
Kett
 
M.M.
Teichman
 
E.
Sampson
 
A.K.
Widdop
 
R.E.
Evans
 
R.G.
Denton
 
K.M.
 
Gender differences in pressure-natriuresis and renal autoregulation, role of the angiotensin type 2 receptor
Hypertension
2011
, vol. 
57
 (pg. 
275
-
282
)
[PubMed]
71
Viegas
 
V.U.
Liu
 
Z.Z.
Nikitina
 
T.
Perlewitz
 
A.
Zavaritskaya
 
O.
Schlichting
 
J.
Persson
 
P.B.
Regitz-Zagrosek
 
V.
Patzak
 
A.
Sendeski
 
M.M.
 
Angiotensin II type 2 receptor mediates sex differences in mice renal interlobar arteries response to angiotensin II
J. Hypertens.
2012
, vol. 
30
 (pg. 
1791
-
1798
)
[PubMed]
72
Hilliard
 
L.M.
Chow
 
C.L.
Mirabito
 
K.M.
Steckelings
 
U.M.
Unger
 
T.
Widdop
 
R.E.
Denton
 
K.M.
 
Angiotensin type 2 receptor stimulation increases renal function in female, but not male, spontaneously hypertensive rats
Hypertension
2014
, vol. 
64
 (pg. 
378
-
383
)
[PubMed]
73
Kemp
 
B.A.
Howell
 
N.L.
Gildea
 
J.J.
Keller
 
S.R.
Padia
 
S.H.
Carey
 
R.M.
 
AT2 receptor activation induces natriuresis and lowers blood pressure
Circ. Res.
2014
, vol. 
115
 (pg. 
388
-
399
)
[PubMed]
74
Xue
 
B.
Zhang
 
Z.
Beltz
 
T.G.
Guo
 
F.
Hay
 
M.
Johnson
 
A.K.
 
Estrogen regulation of the brain renin angiotensin system in protection against angiotensin II-induced sensitization of hypertension
Am. J. Physiol. Heart Circ. Physiol.
2014
, vol. 
307
 (pg. 
H191
-
H198
)
[PubMed]
75
Xue
 
B.
Pamidimukkala
 
J.
Lubahn
 
D.B.
Hay
 
M.
 
Estrogen receptor-alpha mediates estrogen protection from angiotensin II-induced hypertension in conscious female mice
Am. J. Physiol. Heart Circ. Physiol.
2007
, vol. 
292
 (pg. 
H1770
-
H1776
)
[PubMed]
76
Abdulla
 
M.H.
Johns
 
E.J.
 
Nitric oxide impacts on angiotensin AT2 receptor modulation of high-pressure baroreflex control of renal sympathetic nerve activity in anaesthetized rats
Acta Physiol. (Oxf.)
2014
, vol. 
210
 (pg. 
832
-
844
)
[PubMed]
77
Dai
 
S.Y.
Peng
 
W.
Zhang
 
Y.P.
Li
 
J.D.
Shen
 
Y.
Sun
 
X.F.
 
Brain endogenous angiotensin II receptor type 2 protects against DOCA/salt-induced hypertension in female rats
J. Neuroinflammation
2015
, vol. 
12
 pg. 
47
 
[PubMed]
78
Sullivan
 
J.C.
Bhatia
 
K.
Yamamoto
 
T.
Elmarakby
 
A.A.
 
Angiotensin (1–7) receptor antagonism equalizes angiotensin II induced hypertension in male and female spontaneously hypertensive rats
Hypertension
2010
, vol. 
56
 (pg. 
658
-
666
)
[PubMed]
79
Bosnyak
 
S.
Widdop
 
R.E.
Denton
 
K.M.
Jones
 
E.S.
 
Differential mechanisms of ang (1–7)-mediated vasodepressor effect in adult and aged candesartan-treated rats
Int. J. Hypertens.
2012
, vol. 
2012
 pg. 
192567
 
[PubMed]
80
Safari
 
T.
Nematbakhsh
 
M.
Hilliard
 
L.M.
Evans
 
R.G.
Denton
 
K.M.
 
Sex differences in the renal vascular response to angiotensin II involves the Mas receptor
Acta Physiol. (Oxf.)
2012
, vol. 
206
 (pg. 
150
-
156
)
[PubMed]
81
Lewis
 
E.J.
Hunsicker
 
L.G.
Bain
 
R.P.
Rohde
 
R.D.
 
The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group
N. Engl. J. Med.
1993
, vol. 
329
 (pg. 
1456
-
1462
)
82
Li
 
P.K.
Leung
 
C.B.
Chow
 
K.M.
Cheng
 
Y.L.
Fung
 
S.K.
Mak
 
S.K.
Tang
 
A.W.
Wong
 
T.Y.
Yung
 
C.Y.
Yung
 
J.C.
, et al 
Hong Kong study using valsartan in IgA nephropathy (HKVIN), a double-blind, randomized, placebo-controlled study
Am. J. Kidney Dis.
2006
, vol. 
47
 (pg. 
751
-
760
)
[PubMed]
83
McCarthy
 
C.A.
Widdop
 
R.E.
Denton
 
K.M.
Jones
 
E.S.
 
Update on the angiotensin AT2 receptor
Curr. Hypertens. Rep.
2013
, vol. 
15
 (pg. 
25
-
30
)
[PubMed]
84
Steckelings
 
U.M.
Paulis
 
L.
Namsolleck
 
P.
Unger
 
T.
 
AT2 receptor agonists, hypertension and beyond
Curr. Opin. Nephrol. Hypertens.
2012
, vol. 
21
 (pg. 
142
-
146
)
[PubMed]
85
Foulquier
 
S.
Steckelings
 
U.M.
Unger
 
T.
 
Impact of the AT2 receptor agonist C21 on blood pressure and beyond
Curr. Hypertens. Rep.
2012
, vol. 
14
 (pg. 
403
-
409
)
[PubMed]
86
Wan
 
Y.
Wallinder
 
C.
Plouffe
 
B.
Beaudry
 
H.
Mahalingam
 
A.K.
Wu
 
X.
Johansson
 
B.
Holm
 
M.
Botoros
 
M.
Karlen
 
A.
, et al 
Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist
J. Med. Chem.
2004
, vol. 
47
 (pg. 
5995
-
6008
)
[PubMed]
87
Bosnyak
 
S.
Welungoda
 
I.K.
Hallberg
 
A.
Alterman
 
M.
Widdop
 
R.E.
Jones
 
E.S.
 
Stimulation of angiotensin AT2 receptors by the non-peptide agonist, compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats
Br. J. Pharmacol.
2010
, vol. 
159
 (pg. 
709
-
716
)
[PubMed]
88
Oparil
 
S.
Schmieder
 
R.E.
 
New approaches in the treatment of hypertension
Circ. Res.
2015
, vol. 
116
 (pg. 
1074
-
1095
)
[PubMed]
89
Chesley
 
L.C.
Talledo
 
E.
Bohler
 
C.S.
Zuspan
 
F.P.
 
Vascular reactivity to angiotensin II and norepinephrine in pregnant women
Am. J. Obstet. Gynecol.
1965
, vol. 
91
 (pg. 
837
-
842
)
[PubMed]
90
Anton
 
L.
Brosnihan
 
K.B.
 
Systemic and uteroplacental renin angiotensin system in normal and pre-eclamptic pregnancies
Ther. Adv. Cardiovasc. Dis.
2008
, vol. 
2
 (pg. 
349
-
362
)
[PubMed]
91
Hladunewich
 
M.A.
Kingdom
 
J.
Odutayo
 
A.
Burns
 
K.
Lai
 
V.
O'Brien
 
T.
Gandhi
 
S.
Zimpelmann
 
J.
Kiss
 
A.
Miller
 
J.
, et al 
Postpartum assessment of the renin angiotensin system in women with previous severe, early-onset preeclampsia
J. Clin. Endocrinol. Metab.
2011
, vol. 
96
 (pg. 
3517
-
3524
)
[PubMed]
92
Merrill
 
D.C.
Karoly
 
M.
Chen
 
K.
Ferrario
 
C.M.
Brosnihan
 
K.B.
 
Angiotensin-(1–7) in normal and preeclamptic pregnancy
Endocrine
2002
, vol. 
18
 (pg. 
239
-
245
)
[PubMed]
93
Zhou
 
A.
Dekker
 
G.A.
Lumbers
 
E.R.
Lee
 
S.Y.
Thompson
 
S.D.
McCowan
 
L.M.
Roberts
 
C.T.
 
The association of AGTR2 polymorphisms with preeclampsia and uterine artery bilateral notching is modulated by maternal BMI
Placenta
2013
, vol. 
34
 (pg. 
75
-
81
)
[PubMed]
94
Mirabito
 
K.M.
Hilliard
 
L.M.
Wei
 
Z.
Tikellis
 
C.
Widdop
 
R.E.
Vinh
 
A.
Denton
 
K.M.
 
Role of inflammation and the angiotensin type 2 receptor in the regulation of arterial pressure during pregnancy in mice
Hypertension
2014
, vol. 
64
 (pg. 
626
-
631
)
[PubMed]
95
Chen
 
K.
Merrill
 
D.C.
Rose
 
J.C.
 
The importance of angiotensin II subtype receptors for blood pressure control during mouse pregnancy
Reprod. Sci.
2007
, vol. 
14
 (pg. 
694
-
704
)
[PubMed]
96
Carey
 
L.C.
Rose
 
J.C.
 
The midgestational maternal blood pressure decline is absent in mice lacking expression of the angiotensin II AT2 receptor
J. Renin Angiotensin Aldosterone Syst.
2011
, vol. 
12
 (pg. 
29
-
35
)
[PubMed]
97
Takeda-Matsubara
 
Y.
Iwai
 
M.
Cui
 
T.X.
Shiuchi
 
T.
Liu
 
H.W.
Okumura
 
M.
Ito
 
M.
Horiuchi
 
M.
 
Roles of angiotensin type 1 and 2 receptors in pregnancy-associated blood pressure change
Am. J. Hypertens.
2004
, vol. 
17
 (pg. 
684
-
689
)
[PubMed]
98
Bharadwaj
 
M.S.
Strawn
 
W.B.
Groban
 
L.
Yamaleyeva
 
L.M.
Chappell
 
M.C.
Horta
 
C.
Atkins
 
K.
Firmes
 
L.
Gurley
 
S.B.
Brosnihan
 
K.B.
 
Angiotensin-converting enzyme 2 deficiency is associated with impaired gestational weight gain and fetal growth restriction
Hypertension
2011
, vol. 
58
 (pg. 
852
-
858
)
[PubMed]
99
Yamaleyeva
 
L.M.
Pulgar
 
V.M.
Lindsey
 
S.H.
Yamane
 
L.
Varagic
 
J.
McGee
 
C.
daSilva
 
M.
Lopes Bonfa
 
P.
Gurley
 
S.B.
Brosnihan
 
K.B.
 
Uterine artery dysfunction in pregnant ACE2 knockout mice is associated with placental hypoxia and reduced umbilical blood flow velocity
Am. J. Physiol. Endocrinol. Metab.
2015
, vol. 
309
 (pg. 
E84
-
E94
)
[PubMed]
100
Neves
 
L.A.
Stovall
 
K.
Joyner
 
J.
Valdes
 
G.
Gallagher
 
P.E.
Ferrario
 
C.M.
Merrill
 
D.C.
Brosnihan
 
K.B.
 
ACE2 and ANG-(1–7) in the rat uterus during early and late gestation
Am. J. Physiol. Regul. Integr. Comp. Physiol.
2008
, vol. 
294
 (pg. 
R151
-
R161
)
[PubMed]
101
Anton
 
L.
Merrill
 
D.C.
Neves
 
L.A.
Diz
 
D.I.
Corthorn
 
J.
Valdes
 
G.
Stovall
 
K.
Gallagher
 
P.E.
Moorefield
 
C.
Gruver
 
C.
, et al 
The uterine placental bed renin angiotensin system in normal and preeclamptic pregnancy
Endocrinology
2009
, vol. 
150
 (pg. 
4316
-
4325
)
[PubMed]
102
Ferreira
 
V.M.
Gomes
 
T.S.
Reis
 
L.A.
Ferreira
 
A.T.
Razvickas
 
C.V.
Schor
 
N.
Boim
 
M.A.
 
Receptor-induced dilatation in the systemic and intrarenal adaptation to pregnancy in rats
PLoS One
2009
, vol. 
4
 pg. 
e4845
 
[PubMed]
103
Conrad
 
K.P.
 
Emerging role of relaxin in the maternal adaptations to normal pregnancy, implications for preeclampsia
Semin. Nephrol.
2011
, vol. 
31
 (pg. 
15
-
32
)
[PubMed]
104
Hannan
 
R.E.
Davis
 
E.A.
Widdop
 
R.E.
 
Functional role of angiotensin II AT2 receptor in modulation of AT1 receptor-mediated contraction in rat uterine artery, involvement of bradykinin and nitric oxide
Br. J. Pharmacol.
2003
, vol. 
140
 (pg. 
987
-
995
)
[PubMed]
105
Jones
 
E.S.
Vinh
 
A.
McCarthy
 
C.A.
Gaspari
 
T.A.
Widdop
 
R.E.
 
AT2 receptors, functional relevance in cardiovascular disease
Pharmacol. Ther.
2008
, vol. 
120
 (pg. 
292
-
316
)
[PubMed]
106
Weiner
 
C.P.
Lizasoain
 
I.
Baylis
 
S.A.
Knowles
 
R.G.
Charles
 
I.G.
Moncada
 
S.
 
Induction of calcium-dependent nitric oxide synthases by sex hormones
Proc. Natl. Acad. Sci. U.S.A.
1994
, vol. 
91
 (pg. 
5212
-
5216
)
[PubMed]
107
Podymow
 
T.
August
 
P.
 
Update on the use of antihypertensive drugs in pregnancy
Hypertension
2008
, vol. 
51
 (pg. 
960
-
969
)
[PubMed]
108
Stennett
 
A.K.
Qiao
 
X.
Falone
 
A.E.
Koledova
 
V.V.
Khalil
 
R.A.
 
Increased vascular angiotensin type 2 receptor expression and NOS-mediated mechanisms of vascular relaxation in pregnant rats
Am. J. Physiol. Heart Circ. Physiol.
2009
, vol. 
296
 (pg. 
H745
-
H755
)
[PubMed]
109
Ong
 
K.L.
Cheung
 
B.M.Y.
Man
 
Y.B.
Lau
 
C.P.
Lam
 
K.S.L.
 
Prevalence, awareness, treatment, and control of hypertension among United States adults 1999–2004
Hypertension
2007
, vol. 
49
 (pg. 
1999
(pg. 
69
-
2004
)-
75
)
[PubMed]
110
Kearney
 
P.M.
Whelton
 
M.
Reynolds
 
K.
Muntner
 
P.
Whelton
 
P.K.
He
 
J.
 
Global burden of hypertension, analysis of worldwide data
Lancet
2005
, vol. 
365
 (pg. 
217
-
223
)
[PubMed]
111
Wiinberg
 
N.
Hoegholm
 
A.
Christensen
 
H.R.
Bang
 
L.E.
Mikkelsen
 
K.L.
Nielsen
 
P.E.
Svendsen
 
T.L.
Kampmann
 
J.P.
Madsen
 
N.H.
Bentzon
 
M.W.
 
24-h ambulatory blood pressure in 352 normal Danish subjects, related to age and gender
Am. J. Hypertens.
1995
, vol. 
8
 (pg. 
978
-
986
)
[PubMed]
112
Wassertheil-Smoller
 
S.
Anderson
 
G.
Psaty
 
B.M.
Black
 
H.R.
Manson
 
J.
Wong
 
N.
Francis
 
J.
Grimm
 
R.
Kotchen
 
T.
Langer
 
R.
, et al 
Hypertension and its treatment in postmenopausal women, baseline data from the Women's Health Initiative
Hypertension
2000
, vol. 
36
 (pg. 
780
-
789
)
[PubMed]
113
Yanes
 
L.L.
Reckelhoff
 
J.F.
 
Postmenopausal hypertension
Am. J. Hypertens.
2011
, vol. 
24
 (pg. 
740
-
749
)
[PubMed]
114
Fentie
 
I.H.
Greenwood
 
M.M.
Wyss
 
J.M.
Clark
 
J.T.
 
Age-related decreases in gonadal hormones in Long–Evans rats: relationship to rise in arterial pressure
Endocrine
2004
, vol. 
25
 (pg. 
15
-
22
)
[PubMed]
115
Fortepiani
 
L.A.
Zhang
 
H.
Racusen
 
L.
Roberts, 2nd
 
L.J.
Reckelhoff
 
J.F.
 
Characterization of an animal model of postmenopausal hypertension in spontaneously hypertensive rats
Hypertension
2003
, vol. 
41
 (pg. 
640
-
645
)
[PubMed]
116
Maric
 
C.
 
Sex, diabetes and the kidney
Am. J. Physiol. Renal Physiol.
2009
, vol. 
296
 (pg. 
F680
-
F688
)
[PubMed]
117
Baylis
 
C.
 
Sexual dimorphism of the aging kidney: role of nitric oxide deficiency
Physiology
2008
, vol. 
23
 (pg. 
142
-
150
)
[PubMed]
118
Schunkert
 
H.
Danser
 
A.H.
Hense
 
H.W.
Derkx
 
F.H.
Kurzinger
 
S.
Riegger
 
G.A.
 
Effects of estrogen replacement therapy on the renin angiotensin system in postmenopausal women
Circulation
1997
, vol. 
95
 (pg. 
39
-
45
)
[PubMed]
119
Okumura
 
M.
Iwai
 
M.
Nakaoka
 
H.
Sone
 
H.
Kanno
 
H.
Senba
 
I.
Ito
 
M.
Horiuchi
 
M.
 
Possible involvement of AT2 receptor dysfunction in age-related gender difference in vascular remodeling
J. Am. Soc. Hypertens.
2011
, vol. 
5
 (pg. 
76
-
84
)
[PubMed]
120
Wray
 
D.W.
Nishiyama
 
S.K.
Harris
 
R.A.
Richardson
 
R.S.
 
Angiotensin II in the elderly, impact of angiotensin II type 1 receptor sensitivity on peripheral hemodynamics
Hypertension
2008
, vol. 
51
 (pg. 
1611
-
1616
)
[PubMed]
121
Baylis
 
C.
 
Sexual dimorphism, the aging kidney, involvement of nitric oxide deficiency and angiotensin II overactivity
J. Gerontol. A. Biol. Sci. Med. Sci.
2012
, vol. 
67
 (pg. 
1365
-
1372
)
[PubMed]
122
Cao
 
X.J.
Li
 
Y.F.
 
Alteration of messenger RNA and protein levels of cardiac alpha(1)-adrenergic receptor and angiotensin II receptor subtypes during aging in rats
Can. J. Cardiol.
2009
, vol. 
25
 (pg. 
415
-
420
)
[PubMed]
123
Kang
 
A.K.
Miller
 
J.A.
 
Effects of gender on the renin angiotensin system, blood pressure, and renal function
Curr. Hypertens. Rep.
2002
, vol. 
4
 (pg. 
143
-
151
)
[PubMed]
124
Harvey
 
P.J.
Morris
 
B.L.
Miller
 
J.A.
Floras
 
J.S.
 
Estradiol induces discordant angiotensin and blood pressure responses to orthostasis in healthy postmenopausal women
Hypertension
2005
, vol. 
45
 (pg. 
399
-
405
)
[PubMed]
125
Yanes
 
L.L.
Romero
 
D.G.
Iliescu
 
R.
Zhang
 
H.
Davis
 
D.
Reckelhoff
 
J.F.
 
Postmenopausal hypertension, role of the renin angiotensin system
Hypertension
2010
, vol. 
56
 (pg. 
359
-
363
)
[PubMed]
126
Hassager
 
C.
Riis
 
B.J.
Strom
 
V.
Guyene
 
T.T.
Christiansen
 
C.
 
The long-term effect of oral and percutaneous estradiol on plasma renin substrate and blood pressure
Circulation
1987
, vol. 
76
 (pg. 
753
-
758
)
[PubMed]
127
De Lignieres
 
B.
Basdevant
 
A.
Thomas
 
G.
Thalabard
 
J.C.
Mercier-Bodard
 
C.
Conard
 
J.
Guyene
 
T.T.
Mairon
 
N.
Corvol
 
P.
Guy-Grand
 
B.
, et al 
Biological effects of estradiol-17 beta in postmenopausal women, oral versus percutaneous administration
J. Clin. Endocrinol. Metab.
1986
, vol. 
62
 (pg. 
536
-
541
)
[PubMed]
128
Schulman
 
I.H.
Zhou
 
M.S.
Treuer
 
A.V.
Chadipiralla
 
K.
Hare
 
J.M.
Raij
 
L.
 
Altered renal expression of angiotensin II receptors, renin receptor, and ACE-2 precede the development of renal fibrosis in aging rats
Am. J. Nephrol.
2010
, vol. 
32
 (pg. 
249
-
261
)
[PubMed]
129
Heymes
 
C.
Silvestre
 
J.S.
Llorens-Cortes
 
C.
Chevalier
 
B.
Marotte
 
F.
Levy
 
B.I.
Swynghedauw
 
B.
Samuel
 
J.L.
 
Cardiac senescence is associated with enhanced expression of angiotensin II receptor subtypes
Endocrinology
1998
, vol. 
139
 (pg. 
2579
-
2587
)
[PubMed]
130
Proudler
 
A.J.
Ahmed
 
A.I.
Crook
 
D.
Fogelman
 
I.
Rymer
 
J.M.
Stevenson
 
J.C.
 
Hormone replacement therapy and serum angiotensin converting enzyme activity in postmenopausal women
Lancet
1995
, vol. 
346
 (pg. 
89
-
90
)
[PubMed]
131
Groban
 
L.
Pailes
 
N.A.
Bennett
 
C.D.
Carter
 
C.S.
Chappell
 
M.C.
Kitzman
 
D.W.
Sonntag
 
W.E.
 
Growth hormone replacement attenuates diastolic dysfunction and cardiac angiotensin II expression in senescent rats
J. Gerontol. A Biol. Sci. Med. Sci.
2006
, vol. 
61
 (pg. 
28
-
35
)
[PubMed]
132
Hinojosa-Laborde
 
C.
Craig
 
T.
Zheng
 
W.
Ji
 
H.
Haywood
 
J.R.
Sandberg
 
K.
 
Ovariectomy augments hypertension in aging female Dahl salt-sensitive rats
Hypertension
2004
, vol. 
44
 (pg. 
405
-
409
)
[PubMed]