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(Stroke. 2009;40:439.)
© 2009 American Heart Association, Inc.

Original Contributions

Increased Expression of the Transforming Growth Factor-β 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 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.

Correspondence to Imo E. Hoefer, MD, PhD, Laboratory of Experimental Cardiology, University Medical Center Utrecht, 3584 CX Utrecht, Heidelberglaan 100, The Netherlands. E-mail i.hoefer{at}umcutrecht.nl; or Marie-Jose Goumans, PhD, Department of Molecular Cell Biology, Leids University Medical Center, 2333 ZC, Leiden, The Netherlands. E-mail m.j.goumans@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-β (TGFβ) receptor, is a modulator of TGFβ 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 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 TGFβ signaling), EGR-1, and TGFβ 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 TGFβ 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— TGFβ in 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.

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

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