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Submitted on December 9, 2005
Accepted on March 31, 2006
, 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, Department of Surgery and Department of Physiology & Biophysics, Mayo Clinic and Mayo Foundation, Rochester, MN 55905
* To whom correspondence should be addressed. E-mail: lfitzpat{at}amgen.com.
Background: Controversy exists over the association of estrogen and cardiovascular disease. Estrogen receptor 
(ER) and 
(ER) are expressed in the endothelial cells and vascular smooth muscle cells (VSMCs) of many arteries, but the relative importance of ER or ER in mediating the vascular response to estrogens is not well defined, particularly in humans. We have previously shown 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 ER expression in pre- and post-menopausal 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: 9 premenopausal women (PRE), 13 postmenopausal women on hormone therapy (HT) and 33 untreated postmenopausal women (nonHT). Coronary calcification was quantified by contact microradiography and atherosclerotic plaque area was measured histologically. Coronary artery cross-sections were immunostained for ER and ER, and the amount of receptors was estimated semi-quantitatively in each arterial wall layer (intima, adventitia and media). Double immunofluorescence was used to colocalize ER and ER with smooth muscle actin, a marker of VSMCs.
Results: ER and ER were expressed in all artery wall layers, but most avidly in the media (P = 0.001), and co-localized with vascular smooth muscle cells (VSMCs). ER expression exceeded ER expression in all wall layers (P < 0.001), and was adjacent to areas of calcium deposition. ER 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 nonHT 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 ER declined with age (P < 0.01) in HT women only. Age had no effect on ER or ER expression in nonHT or premenopausal women.
Conclusions: ER is the predominant estrogen receptor in human coronary arteries and correlates with coronary calcification, a marker of severe atherosclerosis. Increased ER 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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