Mineralocorticoid and Estrogen Receptors in Endothelial Cells Coordinately Regulate Microvascular Function in Obese Female Mice

Obesity impairs endothelial-mediated vasodilation, the earliest step in vascular disease and a contributor to hypertension. We previously demonstrated that endothelial cell MR (mineralocorticoid receptor) deletion prevents obesity-induced microvascular dysfunction in females by increasing nitric oxide (NO)-mediated vasodilation. ER alpha (Estrogen receptor alpha) can oppose MR function, therefore, we hypothesized that ER alpha mediates the benefits of endothelial MR deficiency. Females lacking endothelial MR or wild-type littermates were fed control or high-fat diet for 20 weeks to cause obesity. MR deletion improved mesenteric artery endothelial-dependent vasodilation in obese females, and ex vivo ER alpha inhibition negated this protective effect. Endothelial MR deletion resulted in significantly more ER alpha mRNA and protein. In vitro, estrogen increased endothelial NO synthase phosphorylation, and this was inhibited by aldosterone and dependent on MR. Both proteins coimmunoprecipitated with striatin and a mimetic peptide that disrupts ER alpha-striatin binding also decreased MR-striatin interaction. Finally, removing endothelial MR in obese females restored endothelial function by increasing the NO component of vasodilation. Combined deletion of endothelial ER alpha negated the benefit of endothelial MR deletion. These results indicate that endothelial ER alpha prevents the detrimental effects of MR in obesity by increasing NO to rescue vasodilation in females. MR and ER alpha may compete for striatin binding within endothelial cells to regulate NO. These data identify a novel mechanism that promotes MR antagonism to prevent obesity-induced microvascular dysfunction in females.

Automated summary

The study showed that deletion of endothelial MR in obese female animals can improve vascular dilation, and endothelial ER alpha plays a positive role in increasing nitric oxide to rescue vasodilation. MR and ER alpha may compete for striatin binding within endothelial cells to regulate NO.