Sex differences in blood pressure regulation and hypertension: renal, hemodynamic, and hormonal mechanisms

Abstract

The teleology of sex differences has been argued since at least as early as Aristotle's controversial Generation of Animals more than 300 years BC, which reflects the sex bias of the time to contemporary readers. Although the question "why are the sexes different" remains a topic of debate in the present day in metaphysics, the recent emphasis on sex comparison in research studies has led to the question "how are the sexes different" being addressed in health science through numerous observational studies in both health and disease susceptibility, including blood pressure regulation and hypertension. These efforts have resulted in better understanding of differences in males and females at the molecular level that partially explain their differences in vascular function and renal sodium handling and hence blood pressure and the consequential cardiovascular and kidney disease risks in hypertension. This review focuses on clinical studies comparing differences between men and women in blood pressure over the life span and response to dietary sodium and highlights experimental models investigating sexual dimorphism in the renin-angiotensin-aldosterone, vascular, sympathetic nervous, and immune systems, endothelin, the major renal sodium transporters/exchangers/channels, and the impact of sex hormones on these systems in blood pressure homeostasis. Understanding the mechanisms governing sex differences in blood pressure regulation could guide novel therapeutic approaches in a sex-specific manner to lower cardiovascular risks in hypertension and advance personalized medicine.

Keywords: blood pressure; dimorphism; hormones; hypertension; sex.

Graphical abstract

FIGURE 1.

Sex differences in blood pressure and related characteristics in the young and old. Premenopausal women exhibit lower blood pressure (BP) and prevalence of hypertension (HTN) than age-matched men; however, these sexual dimorphisms are reversed after menopause, with greater age-related increases in BP and hypertension in postmenopausal women in all races. Both androgen and estrogen may contribute to these age-related sex differences. Estrogen protects young women by suppressing Ang II type 1 receptor (AT1R) activity, inhibiting sodium (Na⁺) reabsorption, and maintaining nitric oxide (NO) bioavailability, but this female-specific protection is lost with estrogen withdrawal after menopause. Of note, although premenopausal women are generally protected from BP and hypertension, they demonstrate higher salt sensitivity of blood pressure (SSBP), which is exacerbated after menopause. Image created with BioRender.com, with permission.

FIGURE 2.

Effects of exogenous hormone therapy and contraception treatment on blood pressure. Gender-affirming hormone therapy in transgender subjects and hormone replacement therapy (HRT) in postmenopausal women cause mixed effects on blood pressure (BP). Oral contraceptives (OCPs) lower BP at lower doses (20–30 μg) but raise BP at high doses (≥50 μg). E₂, 17β-estradiol. Image created with BioRender.com, with permission.

FIGURE 3.

General structure and mechanisms of action for sex hormone receptors. A: modular structure of sex hormone receptors. CTD, COOH-terminal domain; DBD, DNA-binding domain; HRE, hormone response element; LBD, ligand-binding domain; NTD, NH₂-terminal domain. B: genomic and nongenomic actions of sex hormone receptors. AR, androgen receptor; ER, estrogen receptor; GPER, G protein-coupled estrogen receptor; PR, progesterone receptor. Image created with BioRender.com, with permission.

FIGURE 4.

General overview of proposed sex differences in the renin-angiotensin-aldosterone system. Male sex is found to have greater circulating renin, angiotensin-converting enzyme (ACE) activity, and Ang II type 1 receptor (AT1R) activation, implicating testosterone and/or male sex to favor the pressor arm of the renin-angiotensin-aldosterone system (RAAS). Females have greater expression of ACE2, Ang(1–7), and expression of Ang II type 1 receptor (AT2R) and Mas receptor (MasR), suggesting that females have a greater expressions and activation of the depressor arm of the RAAS. Of note, both ACE2 and AT2R genes are located on the X chromosome, and their expression may therefore be influenced by sex chromosome. Green box represents increased expression/activity; red box signifies decreased expression/activity. APA, aminopeptidase A; APN, aminopeptidase N. Image created with BioRender.com, with permission.

FIGURE 5.

Overview of proposed sex differences in renal sodium handling. Preclinical data suggest that males have a greater propensity for sodium reabsorption in the proximal tubule (PT), whereas females have higher expression of active sodium transporters in the distal nephron. Androgens have been shown to increase the expression of renin-angiotensin-aldosterone system (RAAS) components and the sodium/hydrogen exchanger 3 (NHE3) transporter in the proximal tubule, providing a possible mechanism by which males have greater sodium reabsorption in the proximal nephron. Females have been found to have more active sodium transporters [Na⁺-K⁺-2Cl⁻ cotransporter (NKCC)2, sodium-chloride cotransporter (NCC), and epithelial sodium channel ENaC)] and their activating kinase (p-SPAK) in the thick ascending limb of Henle (TAL), distal convoluted tubule (DCT), and connecting tubule and collecting duct (CNT/CD). G, glomeruli; Org, organic anions. Image created with BioRender.com, with permission.

FIGURE 6.

Genomic and nongenomic mechanisms of estrogen-mediated eNOS activation and vasodilation. Ligand [17β-estradiol (E₂) or synthetic compounds] binding to estrogen receptor (ER)α and/or ERβ induces homo- or heterodimerization and nuclear translocation. The ligand-ER complex interacts with the estrogen response element (ERE) on endothelial nitric oxide synthase (eNOS) and other target genes to induce their transcription. E₂ also elicits nongenomic signaling through membrane-bound ER and G protein-coupled estrogen receptor (GPER) to transactivate the epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase (ERK)1/2, and Akt pathways, resulting in eNOS phosphorylation (Ser1177), nitric oxide (NO) production, and vasodilation. Image created with BioRender.com, with permission.

FIGURE 7.

Sex differences in endothelin-1 expression and actions. Endothelin-1 (ET-1) levels exhibit sex differences and are regulated by sex hormones. Estrogen promotes ET-1 expression by activating the estrogen receptor (ER)-nitric oxide (NO) axis and by inhibiting Ang II-reactive oxygen species (ROS). Although ET_A receptor activation induces larger vasocontraction in males, it has greater natriuretic effects in females through G protein-coupled estrogen receptor (GPER)1 and nitric oxide synthase (NOS)1 mechanisms. ET_B activation causes vasoconstriction in males but produces endothelial (e)NOS-mediated vasodilation in females. The vasodilatory effects of ET_B require endogenous estrogen and are inhibited by exogenous or excess androgen. Red arrows indicate deleterious effects; blue arrows indicate protective effects. E₂, 17β-estradiol; OVX, ovariectomy. POS, polycystic ovarian syndrome. Image created with BioRender.com, with permission.

FIGURE 8.

Sex-dependent mechanisms in sympathetic nerve activity. Premenopausal women have higher baroreceptor reflex sensitivity (BRS) and lower sympathetic outflow than postmenopausal women and age-matched men. Hormone replacement therapy (HRT) improves BRS in postmenopausal women. Estrogen activates estrogen receptor (ER)α/β in key brain regions to improve BRS and suppress sympathetic nerve activity. Lower BRS is associated with higher sympathetic outflow in males, which promotes neurogenic hypertension through cardiac, vascular, renal, and adrenal mechanisms. DOCA, deoxycorticosterone acetate; E₂, 17β-estradiol; Image created with BioRender.com, with permission.

FIGURE 9.

Sex differences in immune regulation of hypertension. A: hypertensive stimuli drive the initiation of adaptive immunity, activating antigen presenting cells (APC) to drive T cell-mediated responses that are sex specific, with more pronounced prohypertensive effects via T helper (Th)1/Th17 pathway in males and higher antihypertensive, anti-inflammatory T regulatory (Treg) responses in females. HTN, hypertension. B: adoptive transfer experiments revealed specifically that the CD8 subpopulation of T cells promote hypertension, likely via IL-17A that mediates vasoconstriction, leading to renovascular dysfunction, and cytokines including interferon-γ (IFN-γ), IL-17A, and IL-6, increased sodium/hydrogen exchanger 3 (NHE3)/sodium-chloride cotransporter (NCC)/epithelial sodium channel (ENaC) activity, leading to increased sodium reabsorption, ultimately resulting in hypertension and end-organ damage. DOCA, deoxycorticosterone acetate; ROS, reactive oxygen species. Image created with BioRender.com, with permission.

FIGURE 10.

Mechanisms of salt sensitivity of blood pressure. A: vasodysfunction theory of salt sensitivity of blood pressure (SSBP), which disproportionally affects women. Impaired systemic vasodilation, rather than greater sodium balance or fluid expansion, accounts for arterial pressure elevation during acute salt loading (348, 380, 381). AP, arterial pressure; BW, body weight; HSD, high-salt diet; SVR, systemic vascular resistance. B: vasodysfunction framework is supported by recent novel regulators, collectrin, cullin3 (CUL3), and PPARγ, that mediate endothelial cell (EC) nitric oxide (NO) biogenesis and smooth muscle NO responsiveness. In the endothelium (EC), collectrin facilitates the uptake of endothelial nitric oxide synthase (eNOS) substrate l-arginine by increasing the expression of cationic amino acid transporters in the plasma membrane, while CUL3 maintains eNOS activity by ubiquitinating and degrading protein phosphatase 2 A (PP2A) that dephosphorylates eNOS-Ser1177. In the vascular smooth muscle (SMC), PPARγ effectors CUL3-RhoBTB1 facilitate NO-cGMP signaling by degrading phosphodiesterase 5 (PDE5). PPARγ also promotes E-prostanoid receptor 2 (EP2)-mediated vasodilation by suppressing the expression of the vasoconstrictive EP3. PGE₂, prostaglandin E₂; PKG, protein kinase G; RhoBTB1, Rho-Related BTB Domain Containing 1; sGC, soluble guanylyl cyclase; Ub, ubiquitin. C: deficiencies in vascular collectrin, CUL3, or PPARγ impair systemic vasodilation, decrease renal blood flow (RBF), and increase SSBP. Green box indicates the sex that is more affected. In B and C, blue denotes protective mechanisms and red indicates pathogenic events leading to SSBP. Image created with BioRender.com, with permission.