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(Hypertension. 2004;43:918.)
© 2004 American Heart Association, Inc.

Brief Reviews

Novel Mechanisms Responsible for Postmenopausal Hypertension

Jane F. Reckelhoff; Lourdes A. Fortepiani

From the Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson.

Correspondence to Dr Jane F. Reckelhoff, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216. E-mail jreckelhoff{at}physiology.umsmed.edu

	Abstract

Top Abstract Introduction Animal Model for the... Characterization of the... Possible Mechanisms Responsible... Does Oxidative Stress Play... Does Endothelin Play a... Does the RAS Play... Does Obesity Play a... Does Activation of the... Summary References

 
Blood pressure increases in many women after menopause. Hypertension is one of the major risk factors for cardiovascular disease. However, the mechanisms responsible for the postmenopausal increase in blood pressure are yet to be elucidated. Various humoral systems have been proposed to play a role in postmenopausal hypertension, such as changes in estrogen/androgen ratios, increases in endothelin and oxidative stress, and activation of the renin-angiotensin system (RAS). In addition, obesity, type II diabetes, and activation of the sympathetic nervous system are common in postmenopausal women and may also play important roles. However, progress in elucidating the mechanisms responsible for postmenopausal hypertension has been hampered by the lack of a suitable animal model. The aging female spontaneously hypertensive rat (SHR) exhibits many of the characteristics found in postmenopausal women. In this review, some of the possible mechanisms that could play a role in postmenopausal hypertension are discussed, as well as the characteristics of the aged female SHR as a model to study.

Key Words: endothelin • renin-angiotensin system • oxidative stress • obesity • diabetes mellitus • sympathetic nervous system

	Introduction

Top Abstract Introduction Animal Model for the... Characterization of the... Possible Mechanisms Responsible... Does Oxidative Stress Play... Does Endothelin Play a... Does the RAS Play... Does Obesity Play a... Does Activation of the... Summary References

 
Before menopause, blood pressure is typically lower in women than in age-matched men.¹ In aging men and women, systolic and diastolic blood pressures increase, although in later years the diastolic plateaus or even declines.^1–3 However, in postmenopausal women, the prevalence of hypertension and cardiovascular disease risk increases regardless of ethnic origin. Results from the National Health and Nutrition Examination Survey (NHANES III) showed that in Hispanic women and non-Hispanic black women, the prevalence of hypertension was similar to, or higher than, that in men by age 60 years.⁴ In non-Hispanic white populations, the prevalence of hypertension was higher in women than in men by age 70 years.⁴ The increase in blood pressure in postmenopausal women does not occur as soon as the ovary becomes senescent, but rather over a number of years.⁵ The mechanisms responsible for the increased blood pressure in women after menopause are not known. This review focuses on the use of the spontaneously hypertensive rat as a model of postmenopausal hypertension and evaluates the possible mechanistic roles of the sex hormones, oxidative stress, endothelin, renin-angiotensin system (RAS), weight gain, and sympathetic activation in postmenopausal hypertension.

	Animal Model for the Study of Postmenopausal Hypertension

Top Abstract Introduction Animal Model for the... Characterization of the... Possible Mechanisms Responsible... Does Oxidative Stress Play... Does Endothelin Play a... Does the RAS Play... Does Obesity Play a... Does Activation of the... Summary References

 
The elucidation of mechanisms responsible for postmenopausal hypertension has been stunted by lack of an animal model. Sheep, rabbits, nonhuman primates, rats, and mice have been used as models of various menopausal changes;⁶ however, to our knowledge, there is no animal model of naturally occurring postmenopausal hypertension. There have been attempts to mimic menopause by ovariectomizing animals;^7,8 however, these have rarely taken into account the effect of aging and cessation of ovarian function. In any case, there is no normotensive animal model that exhibits hypertension with aging.

Female spontaneously hypertensive rats (SHR) stop cycling at age 10 to 12 months and have low estradiol levels comparable to postmenopausal women.⁹ As shown in Figure 1, in younger SHR (ages 4 and 8 months), females have lower blood pressure than males.^6,9,10 However, by age 16 to 18 months, the blood pressure has increased by 25 to 35 mm Hg, compared with young females, and 15 mm Hg when compared with 8-month-old females. In addition, the sex difference in blood pressure no longer exists because of the increase in blood pressure in old females, whereas blood pressure in male SHR remains fairly stable after age 8 months.^9,11

View larger version (25K): [in this window] [in a new window]   Figure 1. Mean arterial pressure increases with age in post- cycling female SHR. Blood pressures were measured in male and female SHR via femoral catheters at various ages. *P<0.01, compared with females of same age; P<0.05, compared with females of young ages. Data are redrawn from Fortepiani LA, Zhang H, Racusen LC, Roberts II LJ, Reckelhoff JF. Characterization of an animal model of postmenopausal hypertension in SHR. Hypertension. 2003;41:640–645.

Another hypertensive rat strain that also exhibits increases in blood pressure with aging is the Dahl salt-sensitive rat. Even when fed a low-salt diet, blood pressure increases with time in males and females. If young female Dahl rats are ovariectomized and fed a high-salt diet, the blood pressure increases to higher levels than in intact females.¹² At what age these animals cease cycling and what happens to their blood pressure after cessation of cycling have not been determined, to our knowledge.

In addition to the rat models of postmenopausal hypertension, the follicular-stimulating hormone receptor knockout mouse has been developed and also exhibits some of the characteristics of postmenopausal women.¹³ These animals have low plasma estradiol levels, hypertension when compared with their wild-type counterparts, hypercholesterolemia, and weight gain.¹³ However, when studied at age 14 to 16 weeks, these animals did not exhibit increased oxidative stress or endothelial dysfunction, factors common to postmenopausal women.¹³

	Characterization of the Postcycling SHR as a Model of Postmenopausal Hypertension

Top Abstract Introduction Animal Model for the... Characterization of the... Possible Mechanisms Responsible... Does Oxidative Stress Play... Does Endothelin Play a... Does the RAS Play... Does Obesity Play a... Does Activation of the... Summary References

 
In addition to reduced levels of estradiol after cessation of cycling, the old female SHR (postmenopausal rat [PMR]), aged 18 months, exhibits a 4-fold increase in serum testosterone compared with young females, aged 4 months (Figure 2).⁹ Some of this increase is age-related, however, because female SHRs that were ovariectomized at age 9 months also had an increase in serum testosterone at age 18 months, but had no further increase in blood pressure after age 8 months.⁹

View larger version (15K): [in this window] [in a new window]   Figure 2. Serum free-testosterone increases with age in naturally postcycling female SHR and ovariectomized female SHR. Studies were performed in young (4 months) and old (18 months) rats. Some rats were ovariectomized at age 8 months. *P<0.05, compared with young females; P<0.05 compared with old ovariectomized females.

Along with the increase in blood pressure with age, the PMR also has a reduction in glomerular filtration rate and renal plasma flow and an increase in renal vascular resistance compared with the less hypertensive ovariectomized females of the same age or when compared with young females (Figure 3).⁹ PMRs also excrete significantly more protein than do young females (Figure 4). When morphology of the kidneys was performed, there was a significant increase in the percentage of glomeruli that exhibit some level of sclerosis compared with ovariectomized females of the same age that exhibit no injury (Reckelhoff and Racusen, unpublished data, 2002).

View larger version (18K): [in this window] [in a new window]   Figure 3. Renal function decreases and renal vascular resistance increases in postcycling female SHR. Changes in glomerular filtration rate (A), renal plasma flow (B), and renal vascular resistance with age in female SHR, aged 4 or 18 months, or females that were ovariectomized at age 9 months and studied at 18 months (ovx-18 months). *P<0.001, compared with females, aged 4 months; P<0.05, compared with old ovariectomized females. Data are redrawn from Fortepiani LA, Zhang H, Racusen LC, Roberts II LJ, Reckelhoff JF. Characterization of an animal model of postmenopausal hypertension in SHR. Hypertension. 2003;41:640–645.

View larger version (22K): [in this window] [in a new window]   Figure 4. Urinary protein excretion increases with age in female SHR. *P<0.001, compared with females, age 4 months. Data redrawn from Fortepiani LA, Zhang H, Racusen LC, Roberts II LJ, Reckelhoff JF. Characterization of an animal model of postmenopausal hypertension in SHR. Hypertension. 2003;41:640–645.

Plasma renin activity (PRA) has been reported to be increased in some postmenopausal women.^14,15 The PMR also has an increase in PRA compared with young females (Figure 5). In contrast, in the aging male SHR, the PRA decreases such that the PRAs are similar in old males and females.⁹

View larger version (22K): [in this window] [in a new window]   Figure 5. PRA increases with age in postcycling female SHR. PRA was measured in female SHR, age 4 or 18 months. *P<0.01, compared with females, aged 4 months. Data are redrawn from Fortepiani LA, Zhang H, Racusen LC, Roberts II LJ, Reckelhoff JF. Characterization of an animal model of postmenopausal hypertension in SHR. Hypertension. 2003;41:640–645.

Oxidative stress is also increased in kidneys and plasma of PMRs. As shown in Figure 6, plasma F₂-isoprostanes were significantly increased in PMRs compared with young females.⁹ Furthermore, treatment of PMRs with vitamins E and C for 8 months, beginning before cessation of cycling, reduced oxidative stress (as measured by reduction in urinary excretion rates of F₂-isoprostanes) and prevented the blood pressure increase (Figure 7).⁹ In old males SHRs, however, vitamins E and C had no effect on blood pressure. Thus, the PMR exhibit many of the characteristics found in postmenopausal women.

View larger version (11K): [in this window] [in a new window]   Figure 6. Plasma F2-isoprostanes increase with age in post- cycling female SHR, age 4 or 18 months. *P<0.0001, compared with females, aged 4 months. Data are drawn from Fortepiani LA, Zhang H, Racusen LC, Roberts II LJ, Reckelhoff JF. Characterization of an animal model of postmenopausal hypertension in SHR. Hypertension. 2003;41:640–645.

View larger version (12K): [in this window] [in a new window]   Figure 7. Chronic treatment with antioxidant vitamins reduces blood pressure in postcycling female SHR. Male and female SHR were administered vitamins E (5000 IU/kg diet) and C (100 mg/L drinking water) or vehicles for 8 months, beginning when they were age 8 months. *P<0.01, compared with untreated rats. Data are drawn from Fortepiani LA, Zhang H, Racusen LC, Roberts II LJ, Reckelhoff JF. Characterization of an animal model of postmenopausal hypertension in SHR. Hypertension. 2003;41:640–645.

	Possible Mechanisms Responsible for Postmenopausal Hypertension: Do Changes in Estrogen/Androgen Ratios Play a Role in Postmenopausal Hypertension?

Top Abstract Introduction Animal Model for the... Characterization of the... Possible Mechanisms Responsible... Does Oxidative Stress Play... Does Endothelin Play a... Does the RAS Play... Does Obesity Play a... Does Activation of the... Summary References

 
Experimentally, estradiol has a variety of effects that should be cardiovascular-protective,^16–18 but many of these studies were performed in vitro. However, despite these positive results, hormone replacement therapy (HRT) has not been shown to consistently lower blood pressure in postmenopausal women. As determined by 24-hour ambulatory blood pressure monitoring, HRT typically resulted in changes of only 3 to 4 mm Hg, some at night only, some during the day only.^19–22 The mode of delivery of HRT, whether oral or transdermal, may play a role in its efficacy, but the data are not consistent with which delivery mode is more effective.^20,22 Many of these studies were short-term, ie, <1 year. In contrast, Prelevic et al studied healthy postmenopausal women who had been using HRT for at least 5 years and found that HRT had either no effect or increased blood pressure.²³ Similar findings were reported from the Women’s Health Initiative study, a 5-year study in which HRT increased systolic blood pressure.²⁴ Proponents of the beneficial role of estradiol in cardiovascular disease cite the use of progesterone in HRT as possibly negating the positive effects of estradiol.¹⁶ However, in women who have experienced surgical menopause, estrogen replacement therapy also did not result in significant sustained reductions in blood pressure.^25,26 Further information regarding the efficacy of estrogen treatment alone may come out of the "estrogen only" arm of the Women’s Health Initiative study that is still underway at this writing.²⁴

A relative hyperandrogenic state may play a role in postmenopausal hypertension;^27,28 however, whether androgens are changed in postmenopausal women is still controversial. The conventional wisdom is that androgen levels, like estrogen, decrease with age in men and women. However, Jiroutek et al²⁹ reported that women who were followed for 10 years after cessation of cycling had increases in serum testosterone but decreases in dihydrotestosterone. Similarly, in the Rancho Bernardo cohort, Laughlin et al reported that serum testosterone decreased at first after menopause, but increased with age thereafter, reaching premenopausal levels by age 70 to 79 years.³⁰ As mentioned, the postcycling SHR has a 4-fold increase in serum testosterone compared with young females, consistent with increases in serum testosterone in postmenopausal women.⁹

Therefore, an increase in androgens could play a role in causing postmenopausal hypertension. In support of this hypothesis, premenopausal women with polycystic ovary syndrome or virilizing tumors have elevated serum androgens and increases in blood pressure.^31–33 There are several ways in which androgens could impact blood pressure. Testosterone supplementation in rats stimulates production of angiotensinogen, the substrate for renin, in the kidney, activating the RAS.^34,35 Androgen supplementation in women is also associated with increased plasma endothelin.³⁶ In addition, supplementation of dihydrotestosterone (10^–9 M) in cultured mesangial cells from SHR causes an increase in oxidative stress and increases angiotensin type-1 (AT₁) receptor expression (Cucchiarelli and Reckelhoff, unpublished data, 2003). Thus, androgens could play a role in postmenopausal hypertension by affecting the RAS, endothelin, or oxidative stress.

	Does Oxidative Stress Play a Role in Postmenopausal Hypertension?

Top Abstract Introduction Animal Model for the... Characterization of the... Possible Mechanisms Responsible... Does Oxidative Stress Play... Does Endothelin Play a... Does the RAS Play... Does Obesity Play a... Does Activation of the... Summary References

 
In postmenopausal women, oxidative stress increases, and the longer the time since menopause occurred, the more oxidative stress that is present.^37,38 Furthermore, plasma glutathione peroxidase is reduced, whereas levels of superoxide dismutase are either unchanged or significantly increased.³⁷ As mentioned and as shown in Figure 7, PMR have an increase in oxidative stress, and long-term treatment with vitamins E and C reduces blood pressure,⁹ supporting a role for oxidative stress in mediating postmenopausal hypertension in the SHR.

	Does Endothelin Play a Role in Postmenopausal Hypertension?

Top Abstract Introduction Animal Model for the... Characterization of the... Possible Mechanisms Responsible... Does Oxidative Stress Play... Does Endothelin Play a... Does the RAS Play... Does Obesity Play a... Does Activation of the... Summary References

 
Endothelin is a potent vasoconstrictor that, when administered on a long-term basis, causes increases in sodium reabsorption in the kidney³⁹ and increases blood pressure.^39,40 Endothelin also stimulates oxidative stress by causing upregulation of the subunits of NAD(P)H oxidase and increasing superoxide.⁴¹ In postmenopausal women, plasma endothelin levels have been shown to be increased.⁴² In PMR, preproendothelin mRNA levels in the kidney are also increased compared with premenopausal female SHR (Yanes et al, unpublished data, 2003). In addition, long-term blockade of the endothelin ET_A receptor reduces blood pressure in PMR to levels found in young females. This is unlike young females or old or young male SHR in which ET_A receptor antagonism does not affect blood pressure.^43,44 Thus, endothelin could be playing a role in postmenopausal hypertension in the PMR.

Why plasma endothelin increases in postmenopausal women is not clear. Estradiol inhibits endothelin synthesis.^45,46 Thus, after menopause, this inhibitory effect would be lost. Endothelin synthesis can be upregulated by Ang II,⁴⁷ and ET_A receptors have been shown to mediate Ang II hypertension in animal studies.^48,49 Testosterone treatment of women also increases plasma endothelin levels.³⁶ Just as endothelin can cause oxidative stress, endothelin also increases in response to oxidative stress.⁵⁰ Therefore, endothelin could be increased in postmenopausal women because of reductions in estradiol and increases in Ang II, oxidative stress, or androgens.

	Does the RAS Play a Role in Postmenopausal Hypertension?

Top Abstract Introduction Animal Model for the... Characterization of the... Possible Mechanisms Responsible... Does Oxidative Stress Play... Does Endothelin Play a... Does the RAS Play... Does Obesity Play a... Does Activation of the... Summary References

 
It is commonly thought that PRA, and therefore the activity of the RAS, decreases with age in humans and animals. However, in men and women who had PRA measured serially for 9 years, PRA was higher in postmenopausal women than premenopausal women.^14,15 PRA is also increased in PMR at age 18 months.⁹ Furthermore, treatment of PMR with losartan, an AT1 receptor antagonist, normalizes their blood pressure (Yanes and Reckelhoff, unpublished data, 2004).

The RAS plays a major role in control of blood pressure and body fluid volume (ie, pressure natriuresis).⁵¹ Ang II could also impact blood pressure in postmenopausal women by stimulating synthesis of preproendothelin⁴⁷ or by producing oxidative stress.^52,53 Thus, activation of the RAS not only may cause direct increases in blood pressure but also may stimulate endothelin and oxidative stress to further increase blood pressure in postmenopausal women and rats.

The ovary also has a distinct RAS⁵⁴ and is the major extrarenal source of prorenin and Ang II taken-up by the vasculature in young women.⁵⁵ Although the RAS has been shown to be active in ovaries of fertile women,^56,57 the activity of the RAS in the ovary of postmenopausal women has not been fully elucidated. However, ovarian angiotensin-converting enzyme activity, but not plasma angiotensin-converting enzyme, increases with age in postmenopausal women.⁵⁴ In PMR, ovariectomy at age 16 months almost normalizes blood pressure (Yanes and Reckelhoff, unpublished data, 2004). Therefore, in old female SHR, the ovary very likely contributes some substance that increases their blood pressure, and studies are ongoing to determine the identity of this substance.

	Does Obesity Play a Role in Postmenopausal Hypertension?

Top Abstract Introduction Animal Model for the... Characterization of the... Possible Mechanisms Responsible... Does Oxidative Stress Play... Does Endothelin Play a... Does the RAS Play... Does Obesity Play a... Does Activation of the... Summary References

 
Many, but not all, women gain weight after menopause, and weight gain is associated with increases in blood pressure and increased incidence of type II diabetes.⁵⁸ Obesity is also accompanied by an increase in sympathetic activity,⁵⁹ particularly in the kidney, leading to an increase in renin release that could contribute to hypertension. Therefore, whereas blood pressure increases in most postmenopausal women, obese postmenopausal women have a greater predisposition to hypertension than thinner postmenopausal women. Unfortunately, the PMR gains little weight with age and thus cannot be used to test this hypothesis.

	Does Activation of the Sympathetic Nervous System Play a Role in Postmenopausal Hypertension?

Top Abstract Introduction Animal Model for the... Characterization of the... Possible Mechanisms Responsible... Does Oxidative Stress Play... Does Endothelin Play a... Does the RAS Play... Does Obesity Play a... Does Activation of the... Summary References

 
Aging in humans is associated with increasing sympathetic activity.^60,61 In addition, in obese individuals, whereas total body norepinephrine spillover rates are usually normal, renal norepinephrine spillover is increased.⁵⁹ Thus, with the combination of aging and obesity in postmenopausal women, there may be greater activation of the sympathetic nervous system than in lean aging women. Therefore, an increase in sympathetic tone may play an important role in mediating postmenopausal hypertension.

	Summary

Top Abstract Introduction Animal Model for the... Characterization of the... Possible Mechanisms Responsible... Does Oxidative Stress Play... Does Endothelin Play a... Does the RAS Play... Does Obesity Play a... Does Activation of the... Summary References

 
The mechanisms responsible for increases in blood pressure in postmenopausal women are complex and multifaceted. They are not nearly so simple as a reduction in estradiol. Many studies will be necessary to evaluate the importance of the variety of mechanisms described in this review. Although not perfect, it is hoped that the postmenopausal SHR will provide a suitable animal model in which to quantitatively evaluate some of these mechanisms and that the information could be extrapolated to women.

	Acknowledgments

 
This work was supported by National Institutes of Health HL 66072.

	Footnotes

 
This article was sent to Friedrich C. Luft, associate editor, for review by expert referees, editorial decision, and final disposition.

Received June 23, 2003; first decision July 23, 2003; accepted February 17, 2004.

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