Published Online
on December 12, 2008

A more recent version of this article appeared on February 1, 2009

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Submitted on April 7, 2008
Revised on June 4, 2008
Accepted on June 26, 2008

Increased Expression of the Transforming Growth Factor- Signaling Pathway, Endoglin, and Early Growth Response-1 in Stable Plaques

Pieter T.G. Bot MD; Imo E. Hoefer MD, PhD^*; Joost P.G. Sluijter PhD; Patrick van Vliet MSc; Anke M. Smits MSc; Franck Lebrin PhD; Frans Moll MD, PhD; Jean-Paul de Vries MD, PhD; Pieter Doevendans MD, PhD; Jan J. Piek MD, PhD; Gerard Pasterkamp MD, PhD; and Marie-José Goumans PhD^*

From the Department of Cardiology (P.T.G.B., J.J.P.), AMC Amsterdam, The Netherlands; the Laboratory of Experimental Cardiology (P.T.G.B., I.E.H., G.P.), the Department of Cardiology (J.P.G.S., P.v.V., A.M.S., P.D., M.-J.G.), and the Department of Vascular Surgery (F.M.), UMC Utrecht, Utrecht, The Netherlands; the Department of Vascular Surgery (J.-P.d.V.), St. Antonius Hospital, Nieuwegein, The Netherlands; the Interuniversity Cardiology Institute of the Netherlands (ICIN) (J.P.G.S., P.v.V.), Utrecht, The Netherlands; and Inserm U833 (F.L.), College de France, Paris, France.

^* To whom correspondence should be addressed. E-mail: i.hoefer{at}umcutrecht.nl or m.j.goumans{at}lumc.nl.

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- (TGF) receptor, is a modulator of TGF signaling 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 TGF, stimulates SMC proliferation and collagen synthesis. In atherosclerotic lesions, it is mainly expressed by SMCs. Therefore, we studied the TGF, 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 TGF signaling), EGR-1, and TGF levels 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 TGF signaling (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—TGF in human atherosclerotic plaques is active and signals through the TGF/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.

Key words: collagen • EGR-1 • endoglin • plaque stability • smooth muscle cells

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