Review
Membrane-initiated actions of estrogen on the endothelium

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Abstract

Estrogen-induced rapid, membrane-initiated activation of numerous signal transduction cascades has been shown in animal, cellular and molecular vascular studies, which support the favorable effects of estrogen on vascular structure and function. These effects are mediated by distinct forms of estrogen receptor (ER) α. This includes estrogen-stimulated, rapid activation of endothelial nitric oxide synthase (eNOS), resulting in elaboration of the athero-protective, angiogenesis-promoting product nitric oxide (NO). An N-terminus truncated short isoform of ERα, ER46, plays a critical role in membrane-initiated, rapid responses to 17β-estradiol (E2) in human endothelial cells (ECs). We have proposed a ER46-centered, eNOS-activating molecular complex in human EC caveolar membranes, containing c-Src, phosphatidylinositol 3-kinase (PI3K), Akt and eNOS. In this review, we describe estrogen-induced, rapid, non-genomic actions in the endothelium.

Introduction

Steroid hormones modulate a large number of biological activities in mammals, affecting gene expression, growth and physiology in all organ systems. The cardiovascular system is an important estrogen target. A cardiovascular protective effect of estrogen has been suspected for many years, largely on the basis of the lower incidence of coronary heart disease (CHD) in premenopausal women, relative to that in age-matched males, as well as on the basis of several observational studies (Stamper and Colditz, 1991, Grady et al., 1992). The most basic actions of estrogens were recognized in the 1950s. Jensen and Jacobson concluded that the biological effects of estrogen are mediated by a receptor protein (Jensen and Jacobsen, 1962). The first recognized steroid hormone receptor was an estradiol binding protein (Jensen, 1965), following which Toft and Gorski isolated and characterized an estrogen receptor (ER) from rat uterus (Toft and Gorski, 1966). Pietras and Szego described membrane binding sites for estrogen in endometrial cells (Pietras and Szego, 1977). They partially purified and initially characterized ERs from hepatocyte plasma membranes (Pietras and Szego, 1980). Since that time, estrogen-induced membrane-initiated signaling cascades have been defined. Of note, the rapid cellular action of steroid hormones was first reported in 1942 (Selye, 1942). In this review, we will discuss the importance of ER, especially ER46, in rapid, membrane-initiated effects of estrogen and its signaling in the endothelium.

Section snippets

Estrogen receptor (ER) and ER46

There are two known ER genes encoding classical ERs, ERα and ERβ, initially isolated from breast cancer MCF cells and rat prostate, respectively (Green et al., 1986, Greene et al., 1986, Kuiper et al., 1996). These two ERs share high sequence homology except in their amino terminus, bear similar affinities for estrogen and bind the same DNA response elements. A G protein-coupled 7-transmembrane receptor, GPR30, unrelated to classical ER structure but with high affinity to E2 has also been

Effects of estrogen on the vascular system

Estrogen binds to vascular endothelial and smooth muscle cells with high affinity (Grady et al., 1992, Farhat et al., 1996). Estrogen has numerous nuclear-initiated genomic effects on ECs, including the repression of athero-promoting and the induction of athero-protective genes (Caulin-Glaser et al., 1996, Mendelsohn and Karas, 1999). Estrogen also stimulates rapid activation of vascular endothelial nitric oxide synthase (eNOS) and rapid vasodilation mediated by ERs (Chen et al., 1999,

Localization of ERs at the plasma membrane

Indirect evidence for plasma membrane-associated ERs by cell imaging techniques initially supported the concept of rapid membrane-initiated estrogen responses (Pappas et al., 1995, Ropero et al., 2002, Li et al., 2003). ER localization at the plasma membrane is dependent on posttranslational modification and association with other proteins. We and others have demonstrated that ER palmitoylation is critical for plasma membrane localization (Li et al., 2003, Acconcia et al., 2004, Pedram et al.,

Estrogen and rapid membrane-initiated signaling

The most studied vascular response to E2 is eNOS activation resulting in NO release. Caveolar localization of eNOS is required for its activity (Shaul et al., 1996, Govers and Rabelink, 2001). Myristoylation and palmitoylation of eNOS result in binding to endothelial caveolin-1 (García-Cardeña et al., 1997). eNOS activity is augmented by estrogen in caveolae, but not in non-caveolae, subcellular fractions. This E2-stimulated event is inhibited by the ER antagonist ICI 182,780 (Chambliss et al.,

Selective estrogen receptor modulators (SERMs)

The potentially favorable biological effects of estrogen and ER engagement in the vascular system are recognized, although several randomized clinical trials, including the large Women's Health Initiative (WHI) trial, have either failed to find a benefit, or even shown a detriment, of hormone replacement therapy on the incidence of cardiovascular events, in postmenopausal women (Grodstein et al., 1997, Hulley et al., 1998, Viscoli et al., 2001, Rossouw et al., 2002, Yeboah et al., 2007). Amidst

Conclusions

The estrogen story, with regard to cardiovascular disease prevention, continues to evolve. Simply stated, the numerous favorable effects of estrogen on the endothelium at the cellular and molecular level, many manifested through rapid signaling responses and eNOS activation, should translate, at some level, to beneficial clinical effects. Large, randomized clinical trials have generally studied postmenopausal women, likely with established atherosclerotic disease, thereby obscuring any of

Acknowledgements

This work was supported by the NIH R01 HL61782, T32HL007950 and by the Raymond and Beverly Sackler Foundation.

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