Abstract 096: Progesterone Upregulates Endothelial Mineralocorticoid Receptor Expression Which Predisposes Female Mice to Obesity-Induced Endothelial Dysfunction

Abstract

Compelling evidence indicates a higher efficacy of mineralocorticoid receptor (MR) blockade for the treatment of cardiovascular disease in females with obesity and diabetes than in males, however, the origin of this sex-specific effect is unknown. We have shown that leptin induces endothelial dysfunction in obese female mice via aldosterone-dependent activation of MR and that only female mice develop endothelial dysfunction (vasorelaxation to acetylcholine) in response to aldosterone ex vivo . Therefore, we hypothesized that females express higher endothelial MR (ECMR) expression than males which predisposes females to obesity-associated endothelial dysfunction. RT-PCR analysis in isolated aortic endothelial cells of Balb/C mice revealed a higher NR3C2 (MR gene) expression in females compared to males (2.9±0.5-fold from male, P<0.05), however, no such difference was observed in non-endothelial cells. Similarly, human adipose tissue endothelial cells exhibited higher ECMR mRNA expression than males (2.1±0.1 fold from male). Female sex-hormone suppression (ovariectomy) decreased ECMR expression in female mice (-0.8±0.2-fold from sham), which was restored by progesterone supplementation (-0.1±0.1-fold from sham). NR3C2 mRNA gradually increased with progesterone in diestrous (1.6±0.1-fold from estrous) phase and increased further in pregnancy day 16 (9.2±0.2-fold from estrous). Furthermore, progesterone dose-dependently increased ECMR protein expression in human endothelial cells in vitro (P<0.05). Increases in ECMR associated with higher progesterone levels in diestrus and pregnant females were associated with an increased sensitivity to leptin-induced endothelial dysfunction in mice. In parallel, while leptin induced endothelial dysfunction in intact ECMR female mice (P<0.05), specific deletion of MR in endothelial cells protected female mice from leptin-induced endothelial dysfunction. These data indicate that progesterone drives the sex-difference in the levels of ECMR expression and predisposes female mice to leptin-induced endothelial dysfunction. In addition, these data provide a rational for the higher efficacy of MR blockade in obese and diabetic women suffering from cardiovascular disease.