TY - JOUR
T1 - Clinically used estrogens differentially inhibit human aortic smooth muscle cell growth and mitogen-activated protein kinase activity
AU - Dubey, Raghvendra K.
AU - Jackson, Edwin K.
AU - Gillespie, Delbert G.
AU - Zacharia, Lefteris C.
AU - Imthurn, Bruno
AU - Keller, Paul J.
PY - 2000/4
Y1 - 2000/4
N2 - Some estrogenic compounds modify vascular smooth muscle cell (SMC) biology; however, whether such effects are mediated in part by estrogen receptors is unknown. The purpose of this study was to evaluate whether the actions of clinically used estrogens on human aortic SMC biology are mediated by estrogen receptors. We examined the effects of various clinically used estrogens in the presence and absence of ICI 182,780, an estrogen receptor antagonist, on cultured human aortic SMC DNA synthesis ([3H]thymidine incorporation), cellular proliferation (cell counting), cell migration (modified Boyden chamber), collagen synthesis ([3H]proline incorporation), and mitogen-activated protein kinase activity. FCS-induced DNA synthesis, cell proliferation, collagen synthesis, platelet-derived growth factor- induced SMC migration, and mitogen-activated protein kinase activity were significantly inhibited by physiological 10-9 mol/L) concentrations of 17β-estradiol and low concentrations (10-8 to 10-7 mol/L) of 17β- estradiol, estradiol valerate, estradiol cypionate, and estradiol benzoate but not by estrone, estriol, 17α-estradiol, or estrone sulfate. The inhibitory effects of 17β-estradiol and other inhibitory estrogens were completely reversed by 100 μmol/L ICI 182,780, and the rank-order potency of various estrogens to inhibit SMC biology matched their rank-order affinity for estrogen receptors. The inhibitory effects of estrogens on SMC biology are in part receptor-mediated. Because the cardioprotective effects of hormone replacement therapy are most likely mediated by modification of SMC biology, whether hormone replacement therapy protects a given postmenopausal woman against cardiovascular disease will depend partially on the affinity of the estrogen for estrogen receptors in vascular SMCs.
AB - Some estrogenic compounds modify vascular smooth muscle cell (SMC) biology; however, whether such effects are mediated in part by estrogen receptors is unknown. The purpose of this study was to evaluate whether the actions of clinically used estrogens on human aortic SMC biology are mediated by estrogen receptors. We examined the effects of various clinically used estrogens in the presence and absence of ICI 182,780, an estrogen receptor antagonist, on cultured human aortic SMC DNA synthesis ([3H]thymidine incorporation), cellular proliferation (cell counting), cell migration (modified Boyden chamber), collagen synthesis ([3H]proline incorporation), and mitogen-activated protein kinase activity. FCS-induced DNA synthesis, cell proliferation, collagen synthesis, platelet-derived growth factor- induced SMC migration, and mitogen-activated protein kinase activity were significantly inhibited by physiological 10-9 mol/L) concentrations of 17β-estradiol and low concentrations (10-8 to 10-7 mol/L) of 17β- estradiol, estradiol valerate, estradiol cypionate, and estradiol benzoate but not by estrone, estriol, 17α-estradiol, or estrone sulfate. The inhibitory effects of 17β-estradiol and other inhibitory estrogens were completely reversed by 100 μmol/L ICI 182,780, and the rank-order potency of various estrogens to inhibit SMC biology matched their rank-order affinity for estrogen receptors. The inhibitory effects of estrogens on SMC biology are in part receptor-mediated. Because the cardioprotective effects of hormone replacement therapy are most likely mediated by modification of SMC biology, whether hormone replacement therapy protects a given postmenopausal woman against cardiovascular disease will depend partially on the affinity of the estrogen for estrogen receptors in vascular SMCs.
KW - Cardiovascular disease mitogen-activated protein kinase
KW - Estrogens
KW - Postmenopausal women
KW - Vascular smooth muscle
UR - http://www.scopus.com/inward/record.url?scp=0034127782&partnerID=8YFLogxK
M3 - Article
C2 - 10764660
AN - SCOPUS:0034127782
SN - 1079-5642
VL - 20
SP - 964
EP - 972
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 4
ER -