Endothelial mineralocorticoid receptors: Novel mechanism for sex-discrepancies in vascular disorders in obesity

The obesity epidemic affects more women than men and obese premenopausal women are at higher risk for development of cardiovascular disease (CVD). The mechanisms that underlie the loss of protection from CVD in young obese women are unknown. The adipose-derived hormone leptin plays a significant role in CVD in obesity. Leptin-mediated sympatho-activation in obese male animals specifically increases blood pressure. In contrast, our lab has published that leptin-induced CVD in females involves activation of the aldosterone-mineralocorticoid receptor (MR) axis. Preliminary data in this proposal demonstrates that there is a sex-discrepancy in vascular aldosterone sensitivity. Our results show that vessels from female mice develop endothelial dysfunction in response to acute aldosterone exposure, whereas those from males do not. In addition, female mice, both lean and obese, have ~3-4-fold higher expression of the endothelial cell mineralocorticoid receptor (ECMR). Suppression of female sex hormones by ovariectomy ablates the sex difference in ECMR expression, which is restored with the hormone progesterone. In addition, female mice with ECMR deletion do not develop leptin-induced endothelial dysfunction. These data suggest that ECMR mediates the increased sensitivity to aldosterone in obese premenopausal females. We hypothesize that ECMR mediate obesity-associated, leptin-induced endothelial dysfunction and hypertension in obese female mice. We will test this hypothesis in two Specific Aims. Specific Aim 1 will determine if ECMR expression is increased in female mice when progesterone levels are endogenously elevated as well whether progesterone receptor inhibition in female obese mice ablates the sex-difference in ECMR expression. We will also determine if progesterone activates MR promoter activity. Specific Aim 2 will assess whether leptin-mediated hypertension and endothelial dysfunction are prevented in ECMR knockout mice. We will also investigate whether ECMR overexpression ablates the sex difference in leptin-induced endothelial dysfunction and hypertension. Collectively, these studies will assess if progesterone mediated increases in ECMR expression are required for leptin-induced CVD in females. These data will increase our knowledge of mechanisms that contribute to CVD in obese premenopausal women, and give evidence for whether pharmacological progesterone inhibition is a potential treatment strategy for CVD in obese women. (AHA Program: Postdoctoral Fellowship)