Activation of Estrogen Receptor-α Reduces Aortic Smooth Muscle Differentiation

Abstract

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-α (ERα) by agonists or by growth factors altered SMC function. To determine the effect of growth factors, estrogen, and ERα expression on SMC differentiation, human aortic SMC were cultured in serum-free conditions for 10 days. SMC from men had lower spontaneous expression of ERα and higher levels of the differentiation markers calponin and smooth muscle α-actin than SMC from women. When SMC containing low expression of ERα were transduced with a lentivirus containing ERα, activation of the receptor by ligands or growth factors reduced differentiation markers. Conversely, inhibiting ERα expression by small interfering RNA (siRNA) in cells expressing high levels of ERα enhanced the expression of differentiation markers. ERα 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 ERα activation switched SMC to a dedifferentiated phenotype and may contribute to plaque instability.