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Research Article

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

¹University of Oklahoma Health Sciences Center

Submitted 12 August 2008 ; revised 13 October 2009 ; accepted in final form 16 October 2009

During platelet-derived growth factor (PDGF)-BB-mediated recruitment to neovascular sprouts, vascular smooth muscle cells (VSMCs) de-differentiate from a contractile to a migratory phenotype. This involves the down-regulation of contractile markers such as smooth muscle (SM) -actin and the up-regulation of pro-migration 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 up-regulation. Here, we provide evidence that the delay in MMP-2 up-regulation may be due to the autocrine expression and activation of transforming growth factor (TGF)-β, which is known to promote the contractile phenotype in VSMCs. While PDGF-BB could induce the loss of stress fibers and focal adhesions, TGF-β was able to block or reverse this transition to a non-contractile state. TGF-β did not, however, suppress early signaling events stimulated by PDGF-BB. Over time, though PDGF-BB induced increased TGF-β1 levels, it suppressed TGF-β2 and TGF-β3 expression, leading to a net decrease in the total TGF-β pool, resulting in the up-regulation of MMP-2. Together, these findings indicate that MMP-2 expression is suppressed by a threshold level of active TGF-β, which in turn promotes a contractile VSMC phenotype that prevents the up-regulation of MMP-2.

platelet-derived growth factor (PDGF)-BB; F-actin cytoskeleton; transforming growth factor (TGF)-beta; phenotypic modulation