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Intimal Estrogen Receptor (ER)ß, But Not ER Expression, Is Correlated with Coronary Calcification and Atherosclerosis in Pre- and Postmenopausal Women

Division of Endocrinology, Metabolism, Diabetes and Nutrition, and Internal Medicine (R.C.C., P.Y.L., S.H., M.R., L.A.F.) and Departments of Surgery and Physiology and Biophysics (V.M.M.), Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Lorraine A. Fitzpatrick, M.D., Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91361. E-mail: lfitzpat{at}amgen.com.

Background: Controversy exists over the association of estrogen and cardiovascular disease. Estrogen receptors (ERs) and ß are expressed in the endothelial cells and vascular smooth muscle cells (VSMCs) of many arteries, but the relative importance of ER or ERß 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 and ERß 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 and ERß, and the amount of receptors was estimated semiquantitatively in each arterial wall layer (intima, adventitia, and media). Double immunofluorescence was used to colocalize ER and ERß with smooth muscle actin, a marker of VSMCs.

Results: ERß and ER were expressed in all artery wall layers, but most avidly in the media (P = 0.001), and colocalized with VSMCs. ERß expression exceeded ER expression in all wall layers (P < 0.001) and was adjacent to areas of calcium deposition. ERß 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 expression did not vary significantly among groups, nor did it correlate with calcium content, plaque area or calcium-to-plaque ratio. Expression of ER but not ERß declined with age (P < 0.01) in HT women only. Age had no effect on ER or ERß expression in non-HT or premenopausal women.

Conclusions: ERß is the predominant ER in human coronary arteries and correlates with coronary calcification, a marker of severe atherosclerosis. Increased ERß 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.

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