Receptor-dependent and genomic-independent actions of estrogen in vascular protection

Functional evidence for a rapid, receptor-dependent and genomic-independent action of estrogen in vascular cells continues to accumulate. Although the nature of the receptor is not yet clear, some of the hormone-induced effects can be blocked by known estrogen antagonists (e.g., ICI 182,780) and can be mimicked by membrane-impermeable forms of estrogen. Because the endothelial output of nitric oxide (NO) is a major regulator of several cardiovascular functions, regulation of NO production has received a lot of attention as a potential mechanism for the cardiovascular protection offered by estrogen. There is ample evidence that estrogen can stimulate NO production and activate endothelial NO synthase (eNOS) both in vitro and in vivo. Recent investigations have shown that estrogen's rapid stimulatory action on eNOS is mediated by the activation of phosphatidylinositol 3-kinase (PI3-K) and protein kinase B (PKB)/Akt pathway among other signaling systems. Although these effects are estrogen receptor-dependent, they are rapid (on the order of a few minutes) and transcription-independent and thus represent genomic-independent but receptor-mediated effects of a steroid operating in vascular cells. In this review, recent evidence for such mechanisms is summarized, and the role of estrogen receptors in vivo is also briefly discussed.