Female sex hormones do not drive the sex-specific mechanisms of obesity-related hypertension.

The global rise in obesity parallels the increasing rates of hypertension and cardiovascular disease (CVD). These trends, and recent clinical and experimental data, have revealed that obesity abolishes the protection from CVD typically conferred by female sex, predisposing young, premenopausal women to vascular dysfunction and hypertension. Findings from our group demonstrated that, in females, obesity induces hypertension via activation of the leptin-aldosterone-mineralocorticoid receptor (MR) axis. However, the origin of this sex-specific mechanism remains unknown. Based on the known effects of estrogen on blood pressure (BP) and vascular function, we tested the contribution of sex hormones. Sham and ovariectomy (OVX) surgeries were conducted in obese female agouti yellow mice to preserve or deplete female sex hormones, respectively. OVX did not significantly alter blood pressure (BP) nor autonomic control of BP or adrenal aldosterone synthase (CYP11B2) expression; however, it impaired endothelial relaxation with no further alterations to vascular function. Chronic leptin receptor blockade decreased BP in both sham and OVX mice and restored endothelium-dependent relaxation, suggesting a lack of contribution of female sex hormones to the mechanism of hypertension. Stimulation of HAC15 and human primary adrenocortical cells with female and male sex steroid hormones did not alter CYP11B2 expression. Furthermore, quantification of CYP11B2 expression in discarded human adrenal glands revealed increases with obesity in women in comparison to men and no alterations with menopause in obese hypertensive women. Collectively, these findings support that female sex hormones do not regulate aldosterone production nor do they drive the sex-specific mechanism underlying obesity-associated hypertension.