Sex-specific Mechanisms Of Obesity-associated Hypertension Are Not Dependent On Ovarian-derived Sex Hormones

Traditionally, female sex hormones were thought to protect premenopausal women from cardiovascular disease, yet recent studies indicate that obesity abolishes these protective effects and predisposes women to vascular dysfunction and hypertension. Previously, our laboratory demonstrated that hypertension in obesity involves the adipokine leptin via sex-specific mechanisms: leptin-mediated sympatho-activation in males and leptin-mediated aldosterone production in females. Novel data gathered from discarded human adrenals indicate that obesity increased aldosterone synthase expression in women. However, whether female sex hormones modulate this sex difference remains unknown. We hypothesized that the loss of ovarian-derived sex hormones induced by ovariectomy (OVX) will alter the mechanism by which obese female mice develop hypertension and impair vascular function. Obese agouti yellow (Ay) mice and lean controls (a/a) underwent OVX or sham (S) surgery. Radiotelemeters were implanted for blood pressure (BP) monitoring at baseline and in response to leptin receptor (LepR) blockade. Mice were euthanized and mesenteric arteries isolated to measure vascular function via wire myography. Obesity increased BP (a/a S : 109±0.9 vs. Ay S : 119±2.5 mmHg, p<0.05) which was not further elevated by OVX (a/a OVX : 103±3.5 vs. Ay OVX : 116±7.5 mmHg). LepR blockade decreased MAP in obese OVX and S mice (Ay S : 112±3.5 vs. Ay OVX : 111±4.2 mmHg), indicating that BP elevation remains leptin-mediated in the absence of female sex hormones. Obesity impaired endothelial-dependent relaxation to acetylcholine (a/a S : 94±6.6, a/a OVX : 95±4.6, Ay S : 82±10, Ay OVX : 71±13%) but OVX did not cause further impairment. OVX did not alter adrenal aldosterone synthase expression nor plasma aldosterone levels. Human adrenocortical cells (HAC15) treated with combination of estradiol ± progesterone exhibited no increased aldosterone synthase expression. These results indicate that loss of ovarian-derived sex hormones does not alter the mechanisms for hypertension in obese female mice. This data suggests that female sex hormones likely play a limited role modulating the sex-specific mechanisms for hypertension in obesity.