Vascular cell signaling by membrane estrogen receptors

There is substantial interest in the effects of estrogen on the vascular wall, due to the marked gender difference in the incidence of clinically apparent coronary heart disease (CHD), when comparing premenopausal women with age-matched males. Recent randomized clinical trials unexpectedly failed to demonstrate a hormone replacement therapy (HRT) benefit for CHD secondary or primary prevention in postmenopausal women. There are several possible explanations for these findings, which have created a conundrum in light of the numerous potentially beneficial vascular effects of estrogen demonstrated at the cellular, molecular, and even animal model level. Clinical trials are ongoing, and the dissection of molecular pathways continues. Although estrogen receptors (ERs) are traditionally defined as ligand-activated transcriptional activators or repressors, a phenomenon certainly involved in some of estrogen's beneficial effects on vascular cells, we and others have recently demonstrated the presence of membrane-associated ERs in endothelial cells (EC), and that engagement of this subset of receptors may also contribute to the favorable molecular profile of the endothelium. In this review, we describe evidence for membrane-localized ERs in EC. We discuss features of their membrane targeting, and how they may differ from classical ERs. We also describe the rapid assembly of a membrane-associated molecular complex, comprised of ER, c-Src and the regulatory unit of phosphatidylinositol 3-kinase (PI3K), p85, in response to estrogen. Finally, we describe how this complex triggers sequential enzyme activation, involving endothelial nitric oxide synthase (eNOS), and consequent enhanced basal release of NO, a key modulator of vascular tone and 'healthy' blood vessels.