Increased expression of the transforming growth factor-βsignaling pathway, endoglin, and early growth response-1 in stable plaques

Abstract

Background and Purpose-Unstable atherosclerotic plaques are characterized by increased macrophages and reduced smooth muscle cells (SMCs) and collagen content. Endoglin, an accessory transforming growth factor-β(TGFβ) receptor, is a modulator of TGFβsignaling recently found to be expressed on SMCs in atherosclerotic plaques. Its function in plaque SMCs and plaque development is unknown. Early growth response-1 (EGR-1), a transcription factor downstream of TGFβ, stimulates SMC proliferation and collagen synthesis. In atherosclerotic lesions, it is mainly expressed by SMCs. Therefore, we studied the TGFβ, endoglin, and EGR-1 pathway in advanced atherosclerotic plaques in relation to plaque phenotype. Methods-Human carotid atherosclerotic plaques (n= 103) were collected from patients undergoing carotid endarterectomy. Histologically, plaques were analyzed for plaque characteristics, ie, collagen, macrophage and SMC content, and intraplaque thrombus. Intraplaque endoglin, pSmad (indicative for TGFβsignaling), EGR-1, and TGFβlevels were analyzed using Western blots and enzyme-linked immunosorbent assays, respectively. Results-Higher endoglin and EGR-1 protein levels correlated positively with increased plaque collagen levels, increased smooth muscle cell content, and decreased intraplaque thrombi as well as TGFβsignaling (pSmad). Although EGR-1 overexpression in vitro stimulated collagen synthesis, inhibiting endoglin resulted in lower EGR-1 levels, decreased SMC proliferation, and decreased collagen content. Conclusions-TGFβin human atherosclerotic plaques is active and signals through the TGFβ/Smad pathway. For the first time, we show a strong association between endoglin and EGR-1, increased collagen and SMCs expression, decreased levels of intraplaque thrombosis, and a stable plaque phenotype. © 2009 American Heart Association, Inc.