Striatin-Dependent Membrane Estrogen Receptor Signaling and Vasoprotection by Estrogens

It is well known that cardiovascular disease is less frequent in premenopausal women compared with men but rises rapidly in postmenopausal women. Such early observations led to the hypothesis that estrogen therapy will reduce the risk of postmenopausal women developing cardiovascular disease.1 However, observational studies have led to conflicting results, with some studies reporting reductions in cardiovascular disease in postmenopausal women taking estrogens, whereas others observed no beneficial effects.2 Rather, increases in the risk of coronary heart disease and stroke have been reported, particularly for women who are older and those with a long hormone-free interval.3 Such findings have led to the speculation that estrogens have competing cardiovascular effects—beneficial and detrimental—and this has intensified efforts to better understand the range of cardiovascular effects mediated by estrogens and their signaling mechanisms, the ultimate aim being to develop new therapies for women that exert the beneficial effects of estrogen while minimizing potentially harmful effects. To achieve this aim, new studies to better understand both nuclear and membrane estrogen receptor (ER)–mediated signaling in target tissues such as the heart and blood vessels, immune cells, and other target tissues are in progress. In this issue of Circulation , Moens and colleagues4 provide novel insights on the importance of membrane ER–mediated signaling pathways in blood vessels for vasoprotection and vascular gene regulation.Article see p 1993Estrogen activates multiple signaling pathways in most target cells and tissues, including those within the cardiovascular system. Functional ERs, ERα and ERβ, are expressed on cardiomyocytes in the heart and by endothelial and smooth muscle cells within blood vessels. Early studies indicated that ERs are ligand-activated transcription factors, which exist primarily in the nucleus complexed with chaperones. On estrogen binding changes in receptor conformation leads to chaperone dissociation and receptor dimerization, followed by DNA binding …