Estrogen and Mechanisms of Vascular Protection

Abstract

Abstract-Estrogen has antiinflammatory and vasoprotective effects when administered to young women or experimental animals that appear to be converted to proinflammatory and vasotoxic effects in older subjects, particularly those that have been hormone free for long periods. Clinical studies have raised many important questions about the vascular effects of estrogen that cannot easily be answered in human subjects. Here we review cellular/molecular mechanisms by which estrogen modulates injury-induced inflammation, growth factor expression, and oxidative stress in arteries and isolated vascular smooth muscle cells, with emphasis on the role of estrogen receptors and the nuclear factor-B (NFB) signaling pathway, as well as evidence that these protective mechanisms are lost in aging subjects. Ovarian Hormones and Cardiovascular Disease in WomenCardiovascular disease is the leading cause of death among women in the United States, and coronary heart disease (CHD) develops in women on average 10 years later than in men. This lag has been attributed, at least in part, to the protective effects of female sex hormones, particularly estrogens (defined as naturally occurring activators of estrogen receptors) before menopause. 1-3 Mechanistic studies carried out in in vitro preparations and in laboratory animals have shown that both natural and synthetic estrogens have antiinflammatory and vasoprotective effects. 4 -18 Further, the natural endogenous estrogen 17␤-estradiol has been shown to cause rapid endotheliumindependent dilation of coronary arteries of men and women, to augment endothelium-dependent relaxation of human coronary arteries ex vivo, and to improve endothelial function as assessed by the brachial artery flow-mediated dilation response in postmenopausal women. 19 Importantly, the latter vasoprotective effects of estrogen have been observed in the early postmenopausal years in both healthy women and those with CHD, but not in older (Ն60 years) postmenopausal women, regardless of the presence or absence of CHD. 19,20 See accompanying article on page 277Observational studies have shown substantial benefit (Ϸ50% reduction in CHD) of hormone therapy in women who choose to use menopausal hormones (and usually begin taking them in the perimenopausal or early postmenopausal period). 21 Randomized controlled trials of menopausal hormone therapy, which typically enroll women 10 years or longer after menopause, after many years of estrogen deprivation, have shown increases in CHD events with hormone treatment (usually conjugated equine estrogenϮa progestin) in this older (60 to 79 years) age group. [22][23][24] In contrast, subgroup analyses of the Women's Health Initiative have shown that women in whom hormone therapy was initiated at a younger age (50 to 59 years), and earlier post menopause tended to have reduced risk of CHD and total mortality. 25,26 Use of unopposed conjugated estrogen was associated with lower risk of CHD than combined estrogenϩprogestin (medroxyprogesterone acetate), and an ancillary study sh...

Complementary inhibition of cerebral aneurysm formation by eNOS and nNOS

“…Sex hormone, especially estrogen, is well known to have a vasoprotective and anti-inflammatory effect. 35 As inflammation in arterial walls greatly influence CA formation, 14,36 estrogen with anti-inflammatory effect may have significantly participated in the pathogenesis of CA, resulting in the sex difference of CA formation. Furthermore, we demonstrated that nNOS compensated the eNOS deficiency in cerebral arteries.…”

Enhanced cardiac inflammation and fibrosis in ovariectomized hypertensive rats: a possible mechanism of diastolic dysfunction in postmenopausal women

“…A growing body of evidence implicates vascular inflammation in cardiovascular diseases in postmenopausal hypertensive women. 13,27 Thus, it is possible that estrogen deficiency in postmenopausal women may augment cardiac …”

“…27 Therefore, it is possible that the beneficial effects of estrogen replacement in this study might have been limited in older rats.…”

Sex Differences in Health and Survival

“…The direct effects of estrogen have been mainly attributed to two estrogen receptor subtypes, ERa and ERb, which are located in vascular endothelial and myocardial cells; as well as to a recently discovered third membrane-bound estrogen receptor, the G-protein-coupled estrogen receptor (GPR30) (Babiker et al 2002;Mendelsohn and Karas 2005;Prossnitz and Maggiolini 2009). The existing literature has provided compelling evidence that estrogen has a range of anti-inflammatory and vasoprotective effects, including improving coronary and peripheral endothelial function; reducing ischemia, reperfusion injury, and inflammatory markers; and attenuating cardiac hypertrophy (Babiker et al 2002;Wise et al 2005;Xing et al 2009;Yang and Reckelhoff 2011).…”