The Vascular Networking of Estrogen

Assessing benefits and risks of estrogen and hormone replacement therapy in postmenopausal women has been a long story with conflicting results and major changes in paradigms.1,2 Observational studies had consistently demonstrated a reduction in mortality and cardiovascular disease incidence in women on hormone replacement therapy compared to postmenopausal women not on replacement therapy. However, randomized trials have resulted in great disappointment because hormone replacement therapy for primary and secondary prevention of atherosclerotic disease were mostly associated with more risk (thromboembolism, malignancies, stroke) than benefit.1,3,4 However, the estrogen story has not been buried because of convincing preclinical data demonstrating a wide variety of cardiovasculoprotective action of estrogens.5 Among others, estrogen has major impact on the endothelium. The integrity of the endothelium effectively prevents atherosclerotic lesion formation and progression and has therefore come into the focus in vascular research. Estrogens trigger nitric oxide bioavailability through activation of endothelial nitric oxide synthase activity6 and reduce production of reactive oxygen species (Figure).7 Furthermore, estrogens accelerate endothelial cell regeneration after endothelial cell damage by mobilization of endothelial progenitor cells and activation of mature endothelial cells within the vessel wall.8–12 Nonendothelial cell–mediated effects of estrogens include effects on the inflammatory and immune system, the platelet cascade with prevention of arterial thrombosis (but promotion of venous thromboembolism) and beneficial effects on blood pressure (Figure).5 Additionally, novel clinical insights of estrogen replacement therapy have boosted and preserved the interest in estrogen-mediated vasculoprotection. The Women’s Health Initiative trial showed that treatment with conjugated equine estrogens alone could not reduce the risk of cardiovascular events compared with placebo treatment.13 In contrast to an elevated risk after treatment with conjugated equine estrogens plus medroxyprogesterone, the cardiovascular event rate was not increased in the single estrogen treatment group. Moreover, subgroup analyses showed that patients who received estrogens at 60 years with 10 years since menopause had a benefit from hormone replacement with estrogens alone, indicating that hormone therapy may only be effective in women in the early stages of menopause when risk factor burden is lower and atherosclerosis less severe.14 Taken together, as we continue to assemble the pieces of the puzzle of estrogen-mediated mechanisms, the full picture is only very slowly becoming visible. In this issue of Circulation Research, Toutain et al add another important piece to the estrogen puzzle.15 In their study, they investigated the protective role of estrogen in a mouse model of skin ischemia mimicking clinical skin flap surgery. Estrogen deficiency after ovariectomy resulted in a severe necrosis of the skin flap, whereas physiological concentrations of estrogen prevented skin flap necrosis. Further analyses unraveled that estrogen-mediated activation of antiapoptotic pathways (Bcl-2 protein expression) and structural and functional changes on the ultrastructural level (increase in mucinous layer important for the protection of the structural skin integrity, only mild endothelial cell damage with prevention of vascular leakage, remodeling of arteriolar anastomoses) account for the observed effects which finally prevent destruction of the vascular network. The protection of the structural components of the skin vasculature ultimately prevented the necrosis of the skin flaps by accelerated reperfusion conditions. The estrogen action was attributed to the estrogen receptor (ER ) and independently of transforming growth factorand NO availability. If we (boldly) assumed that we could draw a big picture from reports on estrogen effects on cardiovascular, skin, and other tissues, one may appreciate the following important aspects of the study by Toutain et al15 for further attention: