Mechanisms of action of estrogen receptors in vascular cells: relevance for menopause and aging

Estrogen exerts pleiotropic functions on the cardiovascular system through binding to estrogen receptors (ERs). Traditionally, ERs have been recognized as transcription factors regulating the expression of target genes. In the past decades, however, numerous studies have revealed rapid actions of estrogen in different systems, especially in non-reproductive tissues such as the cardiovascular system. At this level, estrogen triggers rapid vasodilatation, exerts anti-inflammatory effects, regulates vascular cell growth and migration, and confers protection to cardiomyocytes. These so-called 'extranuclear actions' do not require gene expression or protein synthesis and are independent of the nuclear localization of ERs. Indeed, some of these actions are elicited by ERs residing at or near the plasma membrane. Through complex interactions with membrane-associated signaling molecules such as ion channels, G proteins and the tyrosine kinase c-Src, liganded extranuclear ERs lead to the activation of downstream cascades such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-OH kinase (PI3K). These cascades are responsible for important cardiovascular actions of estrogen, for instance, the activation of nitric oxide synthesis or the remodeling of the endothelial actin cytoskeleton. Moreover, these cascades play crucial roles in regulating the expression of target proteins implicated in cell proliferation, apoptosis, differentiation, movement and homeostasis. Recent advancements in the characterization of the molecular basis of the extranuclear signaling of estrogen help us to understand the biological functions of estrogen and would be beneficial in elucidating current controversies on estrogen's clinical efficacy in the cardiovascular system.