Activation of Estrogen Receptor- Reduces Aortic Smooth Muscle Differentiation

Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, The Ohio State University, Columbus, Ohio, United States
Circulation Research (Impact Factor: 11.02). 10/2006; 99(5):477-84. DOI: 10.1161/01.RES.0000238376.72592.a2
Source: PubMed


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

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Available from: Mikhail A Gavrilin
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    • "Sex steroid hormones differently impact on VSMC migration. It has been demonstrated that 17b-estradiol (E2) was effective in inhibiting proliferation and migration of human VSMCs induced by growth factors (Dai-Do et al., 1996; Montague et al., 2006), whereas data concerning the relationship between testosterone (Tes) and dihydrotestosterone (DHT) levels and VSMC migration are scanty and, in general, indicate a more dangerous effect of lower Tes levels than high hormone levels (Bain, 2010; Nigro and Christ- Crain, 2012). "
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    ABSTRACT: Sex steroid hormones differently control the major physiological processes in male and female organisms. In particular, their effects on vascular smooth muscle cells (VSMCs) migration are at the root of sex/gender-related differences reported in the cardiovascular system. Several exogenous substances, defined endocrine disruptor chemicals (EDCs), could interfere with these androgen and estrogen effects; however, the sex/gender-related susceptibility of VSMC motility to EDCs is completely unknown. Here, the effect of naturally occurring (naringenin, Nar) and synthetic (bisphenol A, BPA) EDCs on male and female VSMC motility has been evaluated. 17β-estradiol (E2, 0.1 nM to 1 µM) induced a dose-dependent inhibition of motility in female-derived VSMC. In contrast, neither dihydrotestosterone (DHT, 0.01 to 100 nM) nor the common precursor of sex steroid hormones, testosterone (Tes, 0.01 to 100 nM) modified male-derived VSMC motility. Estrogen receptor (ER) β subtype-dependent activation of p38 was necessary for the E2 effect on cell motility. High BPA concentration prevented E2 effects in female-derived cells being without any effect in male-derived cells. Nar mimicked E2 effects on female-derived cells even in the presence of E2 or BPA. Intriguingly, Nar also inhibited the male-derived VSMC mobility. This latter effect was prevented by ERβ inhibitor, but not by the androgen receptor (AR) inhibitor. As a whole, ERβ-dependent signals in VSMC results more susceptible to the impact of EDCs than AR signals suggesting a possible high and overall susceptibility of female to EDCs. However, several male-derived cells, including VSMC, express ERβ which could also serve as target of EDC disruption in male organisms. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Aug 2014 · Journal of Cellular Physiology
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    • "The unbalance of proliferation and apoptosis of vascular smooth muscle cells (VSMC) plays an important role in the development of proliferative vascular diseases such as primary atherosclerosis, postangioplasty restenosis and transplant vasculopathy . Although numerous studies have suggested that in vivo, administration of estrogen significantly suppresses injury-induced arterial intimal hyperplasia through inhibiting VSMC proliferation [2] [3] [4] [5] [6], data from in vitro experiments are conflicting with some studies showing that estrogen inhibits cultured VSMC replication and migration [7] [8] [9] [10] [11] [12] [13] [14], and others that the hormone promotes 3 H-thymidine incorporation or proliferation of the cells [15] [16] [17] [18]. A recent study using aromatase-knockout (ArKO) mouse as an estrogen-deficient animal model showed that VSMC cultured from the ArKO mice had a much lower proliferative response to serum or PDGF- BB than those from the wild-type animals; and the thickness of the aortic medial smooth muscle was approximately 10% less in the ArKO mice than WT male mice at the age of 1 year [15]. "
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    ABSTRACT: To investigate the mechanisms underlying the dual effects of estrogen on vascular smooth muscle cells (VSMC). MTT assay, ELISA, flow cytometry and Western analysis were used to investigate the effects of 17beta-estradiol (E(2)) on proliferation, apoptosis, cell cycle progression, ERK and p38 activities of subcultured rat VSMC with or without chemical block of MEK or p38 kinases. E(2)-promoted VSMC proliferation was accompanied with an increased phosphorylation of ERK1/2, which could be blocked by MEK inhibitor U0126; the E(2)-induced VSMC apoptosis, which appeared mainly in the G2/M phase, was related with the activation of p38 and could be blocked by p38 inhibitor SB203580. More interestingly, MEK inhibition in E(2)-treated VSMC led to an enhanced p38 phosphorylation and a shift of apoptosis from G2/M phase-predominant to G0/G1 phase-predominant; whereas block of p38 increased the E(2)-induced ERK1/2 phosphorylation and proliferation of the VSMC. This reciprocal phenomenon was related with cross-talk between ERK and p38 pathways which might be mediated by MKP-1 and PP2A. The effects of E(2) on proliferation and apoptosis, and their related pathways could be separately induced by the specific agonists of estrogen receptor (ER) alpha and beta alone and inhibited or eliminated by the ER blocker ICI 182,780. The dual effects of estrogen on VSMC involve concurrent activations of ERK and p38 pathways by ER alpha and beta respectively, and the fates of VSMC are determined by the dynamic balance between these two pathways.
    Preview · Article · Jul 2008 · International journal of cardiology
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