Clinically used estrogens differentially inhibit human aortic smooth muscle cell growth and mitogen-activated protein kinase activity

Some estrogenic compounds modify vascular smooth muscle cell (SMC) biology; however, whether such effects are mediated in part by estrogen receptors i s unknown. The purpose of this study was to evaluate whether the actions of clinically used estrogens on human aortic SMC biology are mediated by estr ogen receptors. We examined the effects of various clinically used estrogen s in the presence and absence of ICI 182,780, an estrogen receptor antagoni st, on cultured human aortic SMC DNA synthesis ([H-3]thymidine incorporatio n), cellular proliferation (cell counting), cell migration (modified Boyden chamber), collagen synthesis ([H-3]proline incorporation), and mitogen-act ivated protein kinase activity. FCS-induced DNA synthesis, cell proliferati on, collagen synthesis, platelet-derived growth factor-induced SMC migratio n, and mitogen-activated protein kinase activity were significantly inhibit ed by physiological (10(-9) mol/L) concentrations of 17 beta-estradiol and low concentrations (10(-8) to 10(-7) mol/L) of 17 beta-estradiol, estradiol valerate, estradiol cypionate, and estradiol benzoate but not by estrone, estriol, 17 alpha-estradiol, or estrone sulfate. The inhibitory effects of 17 beta-estradiol and other inhibitory estrogens were completely reversed b y 100 mu mol/L ICI 182,780, and the rank-order potency of various estrogens to inhibit SMC biology matched their rank-order affinity for estrogen rece ptors, The inhibitory effects of estrogens on SMC biology are in part recep tor-mediated, Because the cardioprotective effects of hormone replacement t herapy are most likely mediated by modification of SMC biology, whether hor mone replacement therapy protects a given postmenopausal woman against card iovascular disease will depend partially on the affinity of the estrogen fo r estrogen receptors in vascular SMCs.