Published online before print October 23, 2003, doi: 10.1161/01.RES.0000102867.54523.7F
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Submitted on December 17, 2002
Revised on October 9, 2003
Accepted on October 14, 2003
Mechanisms of Hepatocyte Growth Factor-Mediated Vascular Smooth Muscle Cell Migration
Harry Ma ;
From the Departments of Pathology (H.M., T.M.C., T.K., J.W.B.), Microbiology and Immunology (J.W.B.), and Medicine, Division of Molecular Cardiology (A.W.S.), Albert Einstein College of Medicine, Bronx, NY.
* To whom correspondence should be addressed. E-mail: berman{at}aecom.yu.edu.
The migration of vascular smooth muscle cells (SMCs) from the media into the neointima and their subsequent proliferation is important in the pathogenesis of atherosclerosis. This process is regulated by multiple factors, including growth factors, and involves changes in the interaction of SMCs with the extracellular matrix and in intracellular signaling cascades that regulate cell movement. We demonstrated previously that hepatocyte growth factor (HGF) is expressed in human atherosclerotic plaques. Although HGF has been shown to promote SMC migration, the mechanisms involved in this process have not been characterized fully. In this study, inhibitory antibodies were used to determine which integrins mediated HGF-induced SMC migration. Inhibition of 
1 or 3 integrin resulted in a significant decrease in migration. Subsequent experiments were performed to characterize additional biochemical mechanisms involved in HGF-mediated migration. HGF induced the redistribution of focal adhesions, the activation of focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) and their increased association with 1 and 3 integrins, and the production of promatrix metalloproteinase-2. Migration levels were significantly reduced by cotreatment of SMCs with the extracellular signal regulated kinase 1/2 (ERK1/2) inhibitor, UO126, the p38 inhibitor, SB203580, or the phosphatidylinositol-3 kinase inhibitor, LY294002. In HGF-treated SMCs, focal adhesion redistribution and FAK and Pyk2 activation were decreased by ERK1/2 inhibition. Neither SB2035890 nor LY294002 inhibited HGF-induced ERK1/2 activation. Thus, ERK1/2 signaling may play an important role in HGF-mediated SMC migration by contributing to focal adhesion redistribution and FAK and Pyk2 activation.
Key words: atherosclerosis • smooth muscle cells • migration • integrins • cell signaling
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