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

      American Journal of Physiology - Cell Physiology
      Actins, genetics, Animals, DNA Primers, Down-Regulation, Gene Expression Regulation, Enzymologic, drug effects, Genes, fos, Humans, Macrophage Colony-Stimulating Factor, pharmacology, Matrix Metalloproteinase 2, Muscle Contraction, physiology, Muscle, Smooth, Vascular, cytology, enzymology, Platelet-Derived Growth Factor, Polymerase Chain Reaction, Proto-Oncogene Proteins c-sis, Rats, Rats, Inbred WKY, Recombinant Proteins, Signal Transduction, Tissue Inhibitor of Metalloproteinase-1, Tissue Inhibitor of Metalloproteinase-2, Transforming Growth Factor beta1, Up-Regulation

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          Abstract

          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) alpha-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)-beta, which is known to promote the contractile phenotype in VSMCs. Whereas PDGF-BB could induce the loss of stress fibers and focal adhesions, TGF-beta was able to block or reverse this transition to a noncontractile state. TGF-beta did not, however, suppress early signaling events stimulated by PDGF-BB. Over time, though PDGF-BB induced increased TGF-beta1 levels, it suppressed TGF-beta2 and TGF-beta3 expression, leading to a net decrease in the total TGF-beta pool, resulting in the upregulation of MMP-2. Together, these findings indicate that MMP-2 expression is suppressed by a threshold level of active TGF-beta, which in turn promotes a contractile VSMC phenotype that prevents the upregulation of MMP-2.

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