Published online before print July 27, 2006, doi: 10.1161/01.RES.0000238376.72592.a2
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Submitted on June 2, 2006
Revised on July 3, 2006
Accepted on July 17, 2006
Activation of Estrogen Receptor-
Reduces Aortic Smooth Muscle Differentiation
Christine R. Montague ;
From the Department of Medicine (C.R.M., M.G.H., M.A.G., C.B.M.), Ohio State University College of Medicine, Columbus; Center for Biostatistics (G.S.P.), Ohio State University, Columbus; and School of Medicine (P.J.G.-C.), University of Miami, Fla.
* To whom correspondence should be addressed. E-mail: Clay.Marsh{at}osumc.edu.
Women are at high risk of dying from unrecognized cardiovascular disease. Many differences in cardiovascular disease between men and women appear to be mediated by vascular smooth muscle cells (SMC). Because estrogen reduces the proliferation of SMC, we hypothesized that activation of estrogen receptor-
(ER) by agonists or by growth factors altered SMC function. To determine the effect of growth factors, estrogen, and ER expression on SMC differentiation, human aortic SMC were cultured in serum-free conditions for 10 days. SMC from men had lower spontaneous expression of ER and higher levels of the differentiation markers calponin and smooth muscle -actin than SMC from women. When SMC containing low expression of ER were transduced with a lentivirus containing ER, activation of the receptor by ligands or growth factors reduced differentiation markers. Conversely, inhibiting ER expression by small interfering RNA (siRNA) in cells expressing high levels of ER enhanced the expression of differentiation markers. ER expression and activation reduced the phosphorylation of Smad2, a signaling molecule important in differentiation of SMC and initiated cell death through cleavage of caspase-3. We conclude that ER activation switched SMC to a dedifferentiated phenotype and may contribute to plaque instability.
Key words: apoptosis • cardiovascular disease • gene expression • nuclear receptors • smooth muscle differentiation
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Circ. Res. 2006 99: 459-461.[Full Text] [PDF]
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