Estrogen receptor alpha is a major mediator of 17 beta-estradiol's atheroprotective effects on lesion size in Apoe(-/-) mice

The inhibitory effects of estrogen (17 beta -estradiol) on atherosclerosis have been well documented in numerous animal models, and epidemiological ev idence supports this protective effect in humans. The detailed mechanisms f or this protection are not understood, but most are thought to be mediated through estrogen receptors (ERs), of which two are known (ER alpha and ERP) . To investigate the role of ER alpha in the atheroprotective effect of 17 beta -estradiol(E2), we ovariectomized female mice that lack apoE (AAee) or lack both apoE and ER alpha (alpha alpha ee), and treated half of them wit h E2 for three months. E2 treatment of ovariectomized AAee females dramatic ally reduced the size of the lesions as well as their histological complexi ty. Plasma cholesterol was significantly reduced in this group, although th e observed extent of protection by E2 was greater than could be explained s olely by the change in lipid levels. In contrast, E2 treatment of ovariecto mized alpha alpha ee females caused minimal reduction in lesion size and no reduction in total plasma cholesterol compared with alpha alpha ee mice wi thout E2, demonstrating that ER alpha is a major mediator of the atheroprot ective effect of E2. Nevertheless, E2 treatment significantly reduced the c omplexity of plaques in the alpha alpha ee females, although not to the sam e degree as in AAee females, suggesting the existence of ER alpha -independ ent atheroprotective effects of E2.