Intimal estrogen receptor (ER)β, but not ERα expression, is correlated with coronary calcification and atherosclerosis in pre- and postmenopausal women

Background: Controversy exists over the association of estrogen and cardiovascular disease. Estrogen receptors (ERs) alpha and beta are expressed in the endothelial cells and vascular smooth muscle cells (VSMCs) of many arteries, but the relative importance of ER alpha or ER beta in mediating the vascular response to estrogens is not well defined, particularly in humans. We have shown previously that postmenopausal women receiving hormone therapy (HT) had lower mean coronary artery calcium, plaque area, and calcium-to-plaque ratio compared with untreated women. In this study, we examined coronary artery ER alpha and ER beta expression in pre- and postmenopausal women as a function of plaque area, calcium area, calcium-to-plaque ratio, and estrogen status. Methods: Coronary arteries were obtained at autopsy from a total of 55 women: nine premenopausal women, 13 postmenopausal women on HT and 33 untreated postmenopausal women (non-HT). Coronary calcification was quantified by contact microradiography, and atherosclerotic plaque area was measured histologically. Coronary artery cross-sections were immunostained for ER alpha andER beta, and the amount of receptors was estimated semiquantitatively in each arterial wall layer (intima, adventitia, and media). Double immunofluorescence was used to colocalize ER alpha and ER beta with smooth muscle actin, a marker of VSMCs. Results: ER alpha and ER beta were expressed in all artery wall layers, but most avidly in the media (P = 0.001), and colocalized with VSMCs. ER beta expression exceeded ER alpha expression in all wall layers (P < 0.001) and was adjacent to areas of calcium deposition. ER alpha expression in the intimal layer correlated with calcium content, plaque area, and calcium-to-plaque ratio (all P < 0.01) and tended to be greater in non-HT than in HT women (P = 0.06). ER alpha expression did not vary significantly among groups, nor did it correlate with calcium content, plaque area or calcium-to-plaque ratio. Expression of ER alpha but not ER beta declined with age (P < 0.01) in HT women only. Age had no effect on ER alpha or ER beta expression in non-HT or premenopausal women. Conclusions: ER beta is the predominant ER in human coronary arteries and correlates with coronary calcification, a marker of severe atherosclerosis. Increased ER beta expression is linked to advanced atherosclerosis and calcification independent of age or hormone status. Future pharmacogenetic studies that target this receptor are needed to confirm causality.