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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:225.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Molecular Mechanisms of Collagen Isotype-Specific Modulation of Smooth Muscle Cell Phenotype

A. Wayne Orr; Monica Y. Lee; Julia A. Lemmon; Arif Yurdagul, Jr; Maria F. Gomez; Pamela D. Schoppee Bortz; Brian R. Wamhoff

From the Departments of Pathology and Cell Biology and Anatomy (W.O., A.Y.), Louisiana State University Health Sciences Center at Shreveport; the Department of Clinical Sciences (M.F.G.), Malmö, Lund University, Sweden; the Department of Medicine, Cardiovascular Division, Robert M. Berne Cardiovascular Research Center, The Laboratory of Atherogenesis (M.Y.L., J.A.L., B.R.W., P.D.S.), Biomedical Engineering (M.Y.L., B.R.W.), and the Department of Pharmacology (J.A.L., B.R.W.), the University of Virginia, Charlottesville.

Correspondence to Brian R. Wamhoff, Department of Medicine, Cardiovascular Division, Robert M. Berne Cardiovascular Research Center, The Laboratory of Atherogenesis, The University of Virginia, Charlottesville, VA 22908. E-mail wamhoff{at}virginia.edu

Objective— Smooth muscle cell (SMC) phenotypic modulation, an important component of atherosclerosis progression, is critically regulated by the matrix, with normal components of the healthy SMC matrix limiting modulation and atherosclerosis-associated transitional matrix proteins promoting phenotypic modulation. We sought to determine how collagen IV (which comprises the healthy artery wall) and monomeric collagen I (which comprises atherosclerotic lesions) differentially affect SMC phenotype.

Methods and Results— Plating SMCs on collagen IV resulted in elevated expression of SMC contractility proteins compared to collagen I. Concurrent with enhanced contractile gene expression, collagen IV stimulates binding of SRF to CArG boxes in the promoters of smooth muscle actin and smooth muscle myosin heavy chain. Coll IV also stimulated the expression of myocardin, a critical SRF coactivator required to drive expression of SMC specific genes. In contrast to collagen IV, collagen I stimulated enhanced expression of the inflammatory protein vascular cell adhesion molecule (VCAM)-1. NF-B and NFAT-binding sites in the VCAM-1 promoter are critical for collagen I-mediated expression of VCAM-1 promoter activity. However, only inhibitors of NFAT, not NF-B, were able to reduce collagen I-associated VCAM expression, and collagen I but not collagen IV stimulated NFAT transcriptional activity.

Conclusion— These results show for the first time that collagen IV and collagen I differentially affect smooth muscle phenotypic modulation through multiple pathways.

Key Words: transcription • differentiation • inflammation • NFAT • matrix

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