title: Interstitial flow promotes vascular fibroblast, myofibroblast, and smooth muscle cell motility in 3-D collagen I via upregulation of MMP-1.
abstract: 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 cmH(2)O pressure differential (shear stress, approximately 0.05 dyn/cm(2); flow velocity, approximately 0.5 microm/s; and Darcy permeability, approximately 10(-11) cm(2)) 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.
authors.affiliation: Department of Biomedical Engineering, City College of New York, City University of New York, New York 10031, USA.
authors.forename: Zhong-Dong
authors.initials: ZD
authors.lastname: Shi
authors.forename: Xin-Ying
authors.initials: XY
authors.lastname: Ji
authors.forename: Henry
authors.initials: H
authors.lastname: Qazi
authors.forename: John M
authors.initials: JM
authors.lastname: Tarbell
mesh_terms: D000818:Animals; D017209:Apoptosis; D001794:Blood Pressure; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D005782:Gels; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009336:Necrosis; D010539:Permeability; D011480:Protease Inhibitors / Q000494:pharmacology; D011673:Pulsatile Flow; D034622:RNA Interference; D051381:Rats; D012212:Rheology; D013314:Stress, Mechanical; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D024042:Collagen Type I; D004151:Dipeptides; D005782:Gels; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020781:Matrix Metalloproteinase 1