TGF- suppresses the upregulation of MMP-2 by vascular smooth muscle cells in response to PDGF-BB

Risinger GM Jr, Updike DL, Bullen EC, Tomasek JJ, Howard EW. TGFsuppresses the upregulation of MMP-2 by vascular smooth muscle cells in response to PDGF-BB. Am J Physiol Cell Physiol 298: C191–C201, 2010. First published October 21, 2009; doi:10.1152/ajpcell.00417.2008.—During platelet-derived growth factor (PDGF)-BB-mediated recruitment to neovascular sprouts, vascular smooth muscle cells (VSMCs) dedifferentiate from a contractile to a migratory phenotype. This involves the downregulation of contractile markers such as smooth muscle (SM) -actin and the upregulation of promigration genes such as matrix metalloproteinase (MMP)-2. The regulation of MMP-2 in response to PDGF-BB is complex and involves both stimulatory and inhibitory signaling pathways, resulting in a significant delay in upregulation. Here, we provide evidence that the delay in MMP-2 upregulation may be due to the autocrine expression and activation of transforming growth factor (TGF), which is known to promote the contractile phenotype in VSMCs. Whereas PDGF-BB could induce the loss of stress fibers and focal adhesions, TGFwas able to block or reverse this transition to a noncontractile state. TGFdid not, however, suppress early signaling events stimulated by PDGF-BB. Over time, though PDGF-BB induced increased TGF1 levels, it suppressed TGF2 and TGF3 expression, leading to a net decrease in the total TGFpool, resulting in the upregulation of MMP-2. Together, these findings indicate that MMP-2 expression is suppressed by a threshold level of active TGF, which in turn promotes a contractile VSMC phenotype that prevents the upregulation of MMP-2.