Neurovascular control of blood pressure is influenced by aging, sex, and sex hormones

Abstract

In this review, we highlight that the relationship between muscle sympathetic nerve activity (MSNA) and mean arterial pressure is complex, differs by sex, and changes with age. In young men there is an inverse relationship between MSNA and cardiac output where high MSNA is compensated for by low cardiac output. This inverse relationship is not seen in older men. In young women sympathetic vasoconstriction is offset by β-adrenoreceptor mediated vasodilation, limiting the ability of young women to maintain blood pressure in response to orthostatic stress. However, β-mediated dilation in women is attenuated with age, leading to unopposed α-adrenergic vasoconstriction and a rise in the direct transduction of MSNA into increases in blood pressure. We propose that these changes with age and menopausal status are major contributing factors in the increased prevalence of hypertension in older women. In addition to aging, we highlight that changes in sex hormones in young women (across the menstrual cycle, with oral contraceptive use, or with pregnancy) influence MSNA and the transduction of MSNA into increases in blood pressure. It is likely that the β-adrenergic receptors and/or changes in baroreflex sensitivity play a large role in these sex differences and changes with alterations in sex hormones.

the primary goal of this proceedings article is to highlight differences in blood pressure regulation between men and women, including changes that occur with aging/menopause. Additionally, we will explore issues related to the menstrual cycle, pregnancy, and oral contraceptives. Our focus will be on data collected in humans regarding sympathetic activity, β-adrenergic receptor responsiveness, and neurovascular coupling. This article is based on the presentation at the 2015 APS conference Cardiovascular, Renal and Metabolic Diseases: Physiology and Gender in Annapolis, MD entitled “Autonomic regulation of blood pressure in adult humans: effects of sex and age.”

Autonomic Control of Blood Pressure Differs in Men, Women, and With Aging

There are strong data that support a role for the autonomic nervous system in sex-dependent regulation of blood pressure. We will make the case that peripheral vasoconstrictor responses to sympathetic activity are less robust in young women than in young men. A great example of this is the prevalence of orthostatic intolerance. Orthostatic intolerance is more common in young women than in young men, including an increased risk of syncope [47% of young women vs. 24% of young men; relative risk 1.9 (13)] and reduced tolerance to lower body negative pressure (12). In addition to an increased prevalence of syncope, young women generally have lower blood pressure as well as a lower incidence of hypertension compared with young men (14). For example, young women have approximately half of the drop in mean arterial pressure (MAP) as young men in response to autonomic blockade using trimethaphan (−8 vs.−18 mmHg, women vs. men), suggesting less basal autonomic support of blood pressure in young women compared with young men (10).

Sympathetic nervous system activity in humans, measured as muscle sympathetic nerve activity (MSNA, microneurography), is highly variable between healthy individuals. Interestingly, in young men the fall in MAP with trimethaphan is inversely related to baseline MSNA such that individuals with a large resting MSNA had a large drop in MAP with trimethaphan, but there is no relationship seen in young women (1, 10). Despite these findings, there is no relationship between MSNA and MAP in young men or women [r = 0.01 for men and r = 0.02 for women, P = not significant for both (17)]. This is likely because of complex relationships among MSNA and cardiac output (CO) and/or total peripheral resistance (TPR). In young men, 1) we observe a significant relationship between MSNA and TPR such that individuals with high MSNA also exhibit high TPR (17); 2) the lack of a relationship between MSNA and MAP in young men appears to be because of a balance between TPR and CO; and 3) higher MSNA is related to greater TPR, and normal MAP is maintained through a lower CO per unit MSNA. In contrast to men, in young women, the relationship between MSNA and TPR is nonsignificant (17). The lack of a relationship between MSNA and TPR, and MSNA and CO in young women is likely due to greater β-adrenergic-mediated vasodilation offsetting any α-adrenergic vasoconstriction associated with the sympathetic activity (16, 22). This is based on the following observations: 1) after systemic β-adrenoreceptor blockade, a relationship between MSNA and TPR, and MSNA and CO is observed in young women; 2) women exhibit greater β-mediated vasodilation compared with men (22); and 3) women exhibit less forearm vasoconstriction during brachial artery infusions of norepinephrine than men, and the constriction is augmented during concurrent β-adrenoreceptor blockade (16). Taken together, the differences in the relationships between MSNA and CO/TPR and differing responses to autonomic blockade demonstrate that autonomic control of blood pressure differs between young men and young women.

In contrast with the lack of a relationship between MSNA and MAP in young men and women, there is a significant relationship in men and women over 40 yr of age [men: r = 0.37, P < 0.01; women: r = 0.57, P < 0.01 (30)] The steeper slope of the MSNA versus MAP relationship in women over 40 compared with men suggests a larger role of the autonomic nervous system in blood pressure as women age compared with men. Consistent with the larger role of the autonomic nervous system, older women exhibit a greater fall in MAP in response to autonomic blockade with trimethaphan when compared with men and when compared with young women (1, 10). This suggests that the autonomic nervous system plays a greater role in tonic support of MAP in older women. This is likely the result of a reduced role for the β-adrenoreceptor as women age, including less blunting of the MSNA and TPR relationship via reduced β-adrenoreceptor responsiveness (16–18, 20). In addition, postmenopausal women have greater vasoconstrictor responses to norepinephrine as compared with premenopausal women (16). Consistent with this, the transduction of MSNA into blood pressure increases as women age and declines as men age (3). Thus it may not be surprising that, although the incidence of hypertension increases with age in both women and men, at the age of menopause the incidence of hypertension in women begins to exceed that of men (14). We postulate that this occurs in part because sympathetic activity is rising in both groups, but also because vascular transduction of sympathetic activity into blood pressure accelerates in women as they age.

Additionally, our group has investigated the relationships between diastolic blood pressure (DBP) and MSNA in young women and in postmenopausal women using T50 (DBP at which there is a 50% chance of an MSNA burst occurring). Young women have lower MSNA and a more negative T50 than older women (MSNA: 16 ± 5 vs. 33 ± 10 bursts/min, P < 0.001; respectively; T50: −8 ± 5 vs. +2 ± 5 mmHg, P < 0.001; respectively). This suggests that the young women operate on a lower portion of the baroreflex threshold curve, where there is less than 50% likelihood of an MSNA burst occurring. These data imply that DBP is determined by nonneural as well as sympathetic neural influences in young women. However, the higher T50 in postmenopausal women provides further support to the idea that autonomic support of blood pressure is increased in older women (30a).

When these responses are considered in the context of the age-related increases in MSNA, they explain why the relationship between MSNA and blood pressure becomes significant with aging and is stronger in women than in men. If we integrate these findings with the orthostatic intolerance incidence data in young men and women (13), along with the population blood pressure data (14), a coherent picture emerges. More specifically, sympathetic vasoconstriction is offset in young women due to concurrent β-mediated dilation–limiting their ability to vasoconstrict during orthostatic stress. In older women, this β-mediated dilation is absent, and unopposed α-adrenergic vasoconstriction contributes to the age-related rise in blood pressure (Fig. 1). Importantly, what is unclear at this point is whether these “age-related” changes in women are due to the effects of aging or due to the effects of menopause. In our hands, the impact of age on neurovascular control of blood pressure (independent of changes in sex hormones) could be tested in young normally cycling women versus young women who have undergone early oophorectomy, or in older postmenopausal women versus older postmenopausal women using menopausal hormone therapy.

Fig. 1.

Mechanisms that contribute to the age-related increase in blood pressure in women. Sympathetic vasoconstriction is largely offset by β-adrenoreceptor-mediated vasodilation in young women. With age, β-mediated dilation is reduced, which leads to unopposed α-adrenergic restriction and augments the transduction of SNA into increases in blood pressure. Age-related alterations in β-mediated dilation, α-adrenergic constriction, and vascular transduction are major factors that likely contribute to the increased prevalence of hypertension in women, particularly after the onset of menopause. Estrogen and normal sex-specific conditions, such as the menstrual cycle, pregnancy, and menopause, play an important role in these relationships that is still being elucidated. Age-related changes in nitric oxide and prostaglandin-mediated vasodilation could further raise blood pressure. Additionally, reduction in vasodilator prostaglandins could increase the release of norepinephrine. SNA, sympathetic nervous system activity; α, α-adrenergic receptor; β, β-adrenergic receptor; RAAS, renin-angiotensin-aldosterone system; NO, nitric oxide; PGE₂, prostaglandin E; PGI₂, prostaglandin I₂.

Influence of Menstrual Cycle, Oral Contraceptive Use, and Pregnancy on the Cardiovascular System

In addition to differences in neurovascular control between men and women, MSNA is known to fluctuate throughout the ovarian cycle (28). Specifically, MSNA and plasma norepinephrine levels are higher during the midluteal phase of the menstrual cycle when compared with the early follicular phase (28). These changes are attributed to changes in circulating sex hormone levels (6). Although beyond the scope of this review, the main assumption is that estrogen is the driving sex hormone in modulating vascular function (3, 16, 18); however, there are some data that also support a modulatory effect of progesterone (27, 32) and/or testosterone (5). Future work in determining the main hormone responsible for observed sex differences is warranted. MSNA levels observed during the midluteal phase are associated with levels of circulating estradiol [r = −0.50, P = 0.003 (6)]. However, this is not the case for progesterone concentrations [r = 0.21, P = 0.13 (6)]. Testosterone also fluctuates in females during the menstrual cycle, with its peak during the midluteal phase (9). It is unclear whether fluctuation in testosterone influences MSNA in women, though there is evidence testosterone influences MSNA in men (5). Interestingly, despite changes in sympathetic outflow at different phases of the menstrual cycle, changes in vascular transduction are not observed (28). The lack of changes in vascular transduction across the menstrual cycle is likely due to cycle-dependent fluctuations in β-mediated dilation. For example, β-receptor responsiveness appears to be greater during the mid-phase (22) than during the follicular phase (23). Although definitive studies have not been conducted in humans, it appears that any increases in MSNA during the midluteal phase of the menstrual cycle are likely also met with increases in β-adrenoreceptor-mediated vasodilation–thus offsetting any potential effects on blood pressure and peripheral resistance.

In contrast to natural menstrual cycles, over 80% of American women will use oral contraceptives in their lifetime (2, 25). Oral contraceptive pills are known to modulate female sex hormone levels. Despite this, oral contraceptive pill use does not appear to alter MSNA or plasma norepinephrine levels when studied during the placebo (19) or active pill (29) phases. Even with no change in MSNA with oral contraceptive pill use, blood pressure is higher in pill users (11, 15). Additionally, a prospective study found that hypertension risk is elevated during oral contraceptive use, but this increased risk is reduced following cessation of oral contraceptives. They also found a slightly increased risk of hypertension in past users (8). Higher blood pressure on oral contraceptive users may be due to alterations in vascular transduction, as higher estradiol concentrations (achieved using transdermal 17β-estradiol) are associated with increased vascular transduction (more vasoconstriction/increase in blood pressure for a given sympathetic burst) (34). In contrast, higher progesterone concentrations are associated with decreased vascular transduction (less vasoconstriction for a given sympathetic burst) (4). In addition to possible alterations in vascular transductance, oral contraceptives increase β-adrenoreceptor-mediated vasodilation (24). Another possible mechanism for the normal MSNA in the face of higher BP in oral contraceptive pill users is an impairment in baroreflex function (35). Some studies suggest baroreflex sensitivity is lower during the high hormone (active pill) phase when compared with the low hormone (placebo phase) of oral contraceptive pill use (29, 35). Other studies suggest no changes in baroreflex sensitivity with oral contraceptive pill use (7, 26). Together, these data suggest that oral contraceptive pills may alter neurovascular control; however, more work is needed in this area. One interesting caveat is that if the increases in blood pressure seen in women taking oral contraceptives are generated acutely, the increase in blood pressure is sufficient to almost completely suppress sympathetic activity in most young women (33). The fact that oral contraceptive use is not associated with lower levels of MSNA is consistent with the idea that the relationship between MSNA and blood pressure is reset by these compounds.

Changes in the relationships between hormones and MSNA are also seen in other sex-specific conditions. For example, sympathetic activity is known to increase early (~6 wk gestation) during healthy pregnancies (21) and to be even greater in women with gestational hypertension and preeclampsia at term (21). Despite increases in MSNA, healthy pregnancies are often accompanied by reduced blood pressure and total peripheral resistance. It is thus reasonable to speculate that augmented vascular transduction may then be a contributing factor to hypertensive disorders of pregnancy; however, data to support this idea are currently limited. Despite increases in resting MSNA, women with a history of hypertensive pregnancy have a reduced sympathetic response to upright tilt during subsequent early pregnancy compared with pregnant women without a history of hypertensive pregnancy (31). This finding suggests that these changes in the women with a history of hypertensive pregnancy may be due, instead, to a reduced sympathetic reserve or decreased sympathetic baroreflex sensitivity (31). Much more work in this area is needed. However, it is clear that in many sex-specific conditions there are alterations in sympathetic activity, sympathetic transduction, and the relationship between sympathetic activity and blood pressure along with its determinants (Fig. 1).

Perspectives and Significance

MSNA is highly variable between individuals. Furthermore, MSNA varies across the menstrual cycle, during pregnancy, and with menopause. In addition to changes in MSNA, the transduction of sympathetic activity into peripheral vasoconstriction and finally an increase in blood pressure also differs with aging, sex, and with changes in estrogen and progesterone levels. Vascular transduction decreases in age in men, but increases with age in women. It is likely that the β-adrenergic receptors and/or sympathetic baroreflex sensitivity (along with other factors that regulate sympathetic activity) play very important roles in the observed responses in women. Impairments in the balance between each of these variables likely contribute to increased autonomic support of blood pressure with aging via increased vascular transduction and thus heighten the risk of hypertension. Similar mechanisms and multifactorial relationships likely contribute in clinical conditions such as blood pressure changes with oral contraceptive use and/or hypertensive disorders of pregnancy. Unravelling these interactions in normal sex-specific conditions like pregnancy and menopause, along with how they might be altered and contribute to hypertension will be critical to generate new ideas about sex-specific regulation of blood pressure and treatment of hypertension.

GRANTS

This study was supported by National Heart, Lung, and Blood Institute Grant HL083947 (to M. J. Joyner).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

AUTHOR CONTRIBUTIONS

S.E.B., J.K.L., and M.J.J. analyzed data; S.E.B., J.K.L., S.M.R., and M.J.J. interpreted results of experiments; S.E.B., J.K.L., and S.M.R. prepared figures; S.E.B. and J.K.L. drafted manuscript; S.E.B., J.K.L., S.M.R., and M.J.J. edited and revised manuscript; S.E.B., J.K.L., S.M.R., and M.J.J. approved final version of manuscript; J.K.L. and M.J.J. performed experiments.