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Interstitial flow promotes vascular fibroblast, myofibroblast, and smooth muscle cell motility in 3-D collagen I via upregulation of MMP-1

Department of Biomedical Engineering, City College of New York, City University of New York, New York

Submitted April 16, 2009 ; accepted in final form May 19, 2009

Neointima formation often occurs in regions where the endothelium has been damaged and the transmural interstitial flow is elevated. Vascular smooth muscle cells (SMCs) and fibroblasts/myofibroblasts (FBs/MFBs) contribute to intimal thickening by migrating from the media and adventitia into the site of injury. In this study, for the first time, the direct effects of interstitial flow on SMC and FB/MFB migration were investigated in an in vitro three-dimensional system. Collagen I gels were used to mimic three-dimensional extracellular matrix (ECM) for rat aortic SMCs and FBs/MFBs. Exposure to interstitial flow induced by 1 cmH₂O pressure differential (shear stress, 0.05 dyn/cm²; flow velocity, 0.5 µm/s; and Darcy permeability, 10^–11 cm²) substantially enhanced cell motility. Matrix metalloproteinase (MMP) inhibitor (GM-6001) abolished flow-induced migration augmentation, which suggested that the enhanced motility was MMP dependent. The upregulation of MMP-1 played a critical role for the flow-enhanced motility, which was further confirmed by silencing MMP-1 gene expression. Longer exposures to higher flows suppressed the number of migrated cells, although MMP-1 gene expression remained high. This suppression was a result of both flow-induced tissue inhibitor of metalloproteinase-1 upregulation and increased apoptotic and necrotic cell death. Interstitial flow did not affect MMP-2 gene expression or activity in the collagen I gel for any cell type. Our findings shed light on the mechanism by which vascular SMCs and FBs/MFBs contribute to intimal thickening in regions of vascular injury where interstitial flow is elevated.

matrix metalloproteinase; neointima formation; three-dimensional migration

This article has been cited by other articles:

				Z.-D. Shi, X.-Y. Ji, D. E. Berardi, H. Qazi, and J. M. Tarbell Interstitial flow induces MMP-1 expression and vascular SMC migration in collagen I gels via an ERK1/2-dependent and c-Jun-mediated mechanism Am J Physiol Heart Circ Physiol, January 1, 2010; 298(1): H127 - H135. [Abstract] [Full Text] [PDF]

				V. Rizzo Enhanced interstitial flow as a contributing factor in neointima formation: (shear) stressing vascular wall cell types other than the endothelium Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1196 - H1197. [Full Text] [PDF]