© 2000 American Heart Association, Inc.
Vascular Biology |
Clinically Used Estrogens Differentially Inhibit Human Aortic Smooth Muscle Cell Growth and Mitogen-Activated Protein Kinase Activity
From the Departments of Medicine (R.K.D., E.K.J., D.G.G.) and Pharmacology (E.K.J., L.C.Z.), Center for Clinical Pharmacology, University of Pittsburgh Medical Center, Pittsburgh, Pa, and the Department of Obstetrics and Gynecology (R.K.D., B.I., P.J.K.), Clinic for Endocrinology, University Hospital Zurich, Zurich, Switzerland.
Correspondence to Dr Raghvendra K. Dubey, Department of Obstetrics and Gynecology, Clinic for Endocrinology, D-217, NORD-1, Frauenklinik, University Hospital Zurich, CH-8091 Zurich, Switzerland. E-mail rag{at}fhk.smtp.usz.ch
Abstract—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 17ß-estradiol and low concentrations
(10-8 to 10-7 mol/L) of 17ß-estradiol,
estradiol valerate, estradiol cypionate, and estradiol benzoate but not
by estrone, estriol, 17
-estradiol, or estrone sulfate. The
inhibitory effects of 17ß-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.
Key Words: estrogens • vascular smooth muscle • postmenopausal women • cardiovascular disease • mitogen-activated protein kinase
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