Collagen degradation and platelet-derived growth factor stimulate the migration of vascular smooth muscle cells

Cell migration is a key event in many biological processes and depends on s ignals from both extracellular matrix and soluble motogenic factors. During atherosclerotic plaque development, vascular smooth muscle cells migrate f rom the tunica media to the intima through a basement membrane and intersti tial collagenous matrix and proliferate to form a neointima, Matrix metallo proteinases have previously been implicated in neointimal formation and in this study smooth muscle cell adhesion and migration on degraded collagen h ave been evaluated. Vascular smooth muscle cells adhered to native intact c ollagen type I and to its first degradation by-product, 3/4 fragment (gener ated by collagenase-3 cleavage), unwound at 35 degrees C to mimic physiolog ical conditions. PDGF-BB pretreatment induced a fourfold stimulation of smo oth muscle cell motility on the collagen 3/4 fragment whereas no increase i n smooth muscle cell motility on collagen type I was observed. Cell migrati on on collagen type I was mediated by alpha 2 integrin, whereas PDGF-BB-sti mulated migration on the 3/4 collagen fragment was dependent on alpha v bet a 3 integrin, alpha v beta 3 integrin was organised in clusters concentrate d at the leading and trailing edges of the cells and was only expressed whe n cells were exposed to the 3/4 collagen fragment, Tyrphostin A9, an inhibi tor of PDGF receptor-beta tyrosine kinase activity, resulted in complete ab olition of migration of PDGF-BB treated cells on collagen type I and 3/4 fr agment, These results strongly support the hypothesis that the cellular mig ratory response to soluble motogens can be regulated by proteolytic modific ation of the extracellular matrix.