Estrogen receptor α is a major mediator of 17β-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 evidence supports this protective effect in humans. The detailed mechanisms for 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 with E2 for three months. E2 treatment of ovariectomized AAee females dramatically reduced the size of the lesions as well as their histological complexity. Plasma cholesterol was significantly reduced in this group, although the observed extent of protection by E2 was greater than could be explained solely by the change in lipid levels. In contrast, E2 treatment of ovariectomized alpha alpha ee females caused minimal reduction in lesion size and no reduction in total plasma cholesterol compared with alpha alpha ee mice without E2, demonstrating that ER alpha is a major mediator of the atheroprotective effect of E2. Nevertheless, E2 treatment significantly reduced the complexity of plaques in the alpha alpha ee females, although not to the same degree as in AAee females, suggesting the existence of ER alpha -independent atheroprotective effects of E2.