Fertile women have lower blood pressure and cardiovascular risk than age-matched men, which suggests that estrogens exert cardiovascular protective effects. However, whether 17 ␤-estradiol (E2) blunts aldosterone secretion, and thereby affects the gender dimorphism of blood pressure, is unknown. We therefore sought for the estrogen receptor (ER) subtypes in human adrenocortical tissues ex vivo by performing gene and protein expression studies. We also investigated the effect of E2 on aldosterone synthesis and the involved receptors through in vitro functional experiments in the adrenocortical cells HAC15. We found that in the human adrenal cortex and aldosteroneproducing adenoma cells, the most expressed ERs were the ER␤ and the G protein-coupled receptor-1 (GPER-1), respectively. After selective ER␤ blockade, E2 (10 nmol/L) markedly increased both the expression of aldosterone synthase and the production of aldosterone (ϩ5-to 7-fold vs baseline, P Ͻ .001). Under the same condition, the GPER-1 receptor agonist 1-[4-(6-bromo-benzo (1, 3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c] quinolin-8-yl]-ethanone (G-1) (10 nmol/L) mimicked this effect, which was abrogated by cotreatment with either the GPER-1 receptor antagonist (3aS*,4R*,9bR*)-4-(6-Bro-mo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta[c]quinoline (G-15), or a selective protein kinase A inhibitor 8-Bromo-2-monobutyryladenosine-3,5-cyclic monophosphorothioate, Rp-isomer. Silencing of the ER␤ significantly raised aldosterone synthase expression and aldosterone production. Conversely, silencing of the GPER-1 lowered aldosterone synthase gene and protein expression. Moreover, it blunted the stimulatory effect of E2 on aldosterone synthase that was seen during ER␤ blockade. These results support the conclusion that in humans, E2 inhibits aldosterone synthesis by acting via ER␤. Pharmacologic disinhibition of ER␤ unmasks a potent secretagogue effect of E2 that involves GPER-1 and protein kinase A signaling. (Endocrinology 155: 4296 -4304, 2014) F ertile women are at lower risk of cardiovascular (CV) events and have lower blood pressure (BP) values than age-matched men (1, 2); for example, among hypertensive patients recruited in the ONTARGET trial, women had a 22% lower risk for myocardial infarction than men (3). Therefore, estrogens can decrease BP and thereby CV risk,

Compared to the wild-type APA patients those with KCNJ5 mutations showed more prominent cardiovascular damage. Notwithstanding this, their chances of being cured from the hyperaldosteronism and the high BP, and of regression of left ventricular hypertrophy after adrenalectomy, were not compromised by the presence of these mutations.

Pannexin 1 (Panx1), an ATP-efflux pathway, has been linked with inflammation in pulmonary capillaries. However, the physiological roles of endothelial Panx1 in the pulmonary vasculature are unknown. Endothelial transient receptor potential vanilloid 4 (TRPV4) channels lower pulmonary artery (PA) contractility and exogenous ATP activates of endothelial TRPV4 channels. We hypothesized that endothelial Panx1-ATP-TRPV4 channel signaling promotes vasodilation and lowers pulmonary arterial pressure (PAP). Endothelial, but not smooth muscle, knockout of Panx1 increased PA contractility and raised PAP in mice. Flow/shear stress increased ATP efflux through endothelial Panx1 in PAs. Panx1-effluxed extracellular ATP signaled through purinergic P2Y2 receptor (P2Y2R) to activate protein kinase Ca (PKCa), which in turn activated endothelial TRPV4 channels. Finally, caveolin-1 provided a signaling scaffold for endothelial Panx1, P2Y2R, PKCa, and TRPV4 channels in PAs, promoting their spatial proximity and enabling signaling interactions. These results indicate that endothelial Panx1-P2Y2R-TRPV4 channel signaling, facilitated by caveolin-1, reduces PA contractility and lowers PAP in mice.

The incidence of cardiovascular disease (CVD) is lower in pre-menopausal women but increases with age and menopause compared to similar-aged men. Based on the prevalence of CVD in the post-menopausal women, sex hormone-dependent mechanisms have been postulated to be the primary factors responsible for the protection from CVD in pre-menopausal women. Recent Women's Health Initiative studies, Cochrane review, ELITE and KEEPS studies suggest that beneficial effects of hormone replacement therapy (HRT) are seen in women less than 60 years of age and if initiated in less than ten years of menopause. In contrast, the beneficial effects of HRT are not seen in women greater than 60 years of age and if commenced after ten years of menopause. The higher incidence of CVD and the failure of HRT in post-menopausal aged women could be partly associated with fundamental differences in the vascular structure and function between men and women and in between pre and post-menopausal women, respectively. In this regard, previous studies from human and animal studies identified several sex differences in the vascular function and the associated mechanisms. Female sex hormone 17βEstradiol (17βE) regulates the majority of these mechanisms. In this review, we summarize the sex differences in vascular structure, myogenic properties, endothelial-dependent and -independent mechanisms and the role of 17βE in the regulation of vascular function.