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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1008.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Connective Tissue Growth Factor Is Overexpressed in Complicated Atherosclerotic Plaques and Induces Mononuclear Cell Chemotaxis In Vitro

Iwona Cicha; Atilla Yilmaz; Michael Klein; Dieter Raithel; David R. Brigstock; Werner G. Daniel; Margarete Goppelt-Struebe; Christoph D. Garlichs

From the Medical Clinic II (I.C., A.Y., W.G.D., C.D.G.) and Medical Clinic IV (M.G.-S.), University of Erlangen-Nuremberg, Erlangen, Germany; Department of Vascular Surgery (M.K., D.R.), Clinic Nuremberg, Germany; and Center for Cell and Vascular Biology (D.R.B.), Children’s Research Institute, Columbus, Ohio.

Correspondence to Dr Iwona Cicha, Laboratory of Molecular Cardiology, Medical Clinic II, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany. E-mail Iwona_Cicha{at}yahoo.com

Objective— Atherosclerotic blood vessels overexpress connective tissue growth factor (CTGF) mRNA, but the role of CTGF in atherosclerosis remains controversial. To assess the hypothesis that CTGF is involved in atherosclerotic plaque progression, we investigated CTGF protein expression and distribution in the different types of plaque morphology.

Methods and Results— Serial cross-sections of 45 human carotid plaques were immunohistochemically analyzed for the presence of CTGF protein, neovascularization (von Willebrand factor), macrophages (CD68), and T cells (CD3). The lesions were categorized according to American Heart Association (AHA) classification as fibrous (type IV and V) or complicated plaques (type VI). The levels of CTGF were significantly higher in complicated compared with fibrous plaques (P=0.002). CTGF accumulated particularly in the rupture-prone plaque shoulder and in the areas of neovascularization or infiltration with inflammatory cells. Macrophage-like cells stained positive for CTGF protein in plaques. Subsequent in vitro studies showed that although monocyte-derived macrophages do not produce CTGF on stimulation with transforming growth factor-ß, lipopolysaccharide, or thrombin, they take it up from culture medium. Furthermore, CTGF induces mononuclear cell chemotaxis in a dose-dependent manner.

Conclusion— CTGF protein is significantly increased in complicated compared with fibrous plaques and may enhance monocyte migration into atherosclerotic lesions, thus contributing to atherogenesis.

CTGF protein expression in carotid plaque development was investigated. CTGF levels were significantly increased in vulnerable complicated lesions compared with stable fibrous plaques. CTGF was also shown to act as chemoattractant for human mononuclear cells in vitro, suggesting its importance in atherosclerosis.

Key Words: connective tissue growth factor • atherosclerosis • plaque development • chemotaxis

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