Matrix metalloproteinase-1 and thrombin differentially activate gene expression in endothelial cells via PAR-1 and promote angiogenesis

Am J Pathol. 2008 Dec;173(6):1736-46. doi: 10.2353/ajpath.2008.080512. Epub 2008 Nov 6.

Abstract

Many tumor types express matrix metalloproteinase-1 (MMP-1); its collagenase activity facilitates both tumor cell invasion and metastasis. MMP-1 expression is also associated with increased angiogenesis; however, the exact mechanism by which this occurs is not clear. MMP-1 proteolytically activates protease activated receptor-1 (PAR-1), a thrombin receptor that is highly expressed in endothelial cells. Thrombin is also present in the tumor microenvironment, and its activation of PAR-1 is pro-angiogenic. It is currently unknown whether MMP-1 activation of PAR-1 induces angiogenesis in a similar or different manner compared with thrombin. We sought to determine the mechanism by which MMP-1 promotes angiogenesis and to compare the effects of MMP-1 with those of thrombin. Our results demonstrate that via PAR-1, MMP-1 activates mitogen-activated protein kinase signaling cascades in microvessel endothelial cells. Although thrombin activation of PAR-1 also induces signaling through these pathways, the time-course of activation appears to vary. Gene expression analysis revealed a possible consequence of these signaling differences as MMP-1 and thrombin induce expression of different subsets of pro-angiogenic genes. Furthermore, the combination of thrombin and MMP-1 is more angiogenic than either protease alone. These data demonstrate that MMP-1 acts directly on endothelial cells as a pro-angiogenic signaling molecule and also suggest that the effects of MMP-1 may complement the activity of thrombin to better facilitate angiogenesis and promote tumor progression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biocompatible Materials / metabolism
  • Cell Line
  • Collagen / metabolism
  • Drug Combinations
  • Endothelial Cells / cytology
  • Endothelial Cells / physiology*
  • Enzyme Activation
  • Gene Expression*
  • Humans
  • Laminin / metabolism
  • MAP Kinase Signaling System / physiology
  • Matrix Metalloproteinase 1 / genetics
  • Matrix Metalloproteinase 1 / metabolism*
  • Molecular Sequence Data
  • Neovascularization, Physiologic / physiology*
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Proteoglycans / metabolism
  • Receptor, PAR-1 / genetics
  • Receptor, PAR-1 / metabolism*
  • Thrombin / genetics
  • Thrombin / metabolism*

Substances

  • Biocompatible Materials
  • Drug Combinations
  • Laminin
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Proteoglycans
  • Receptor, PAR-1
  • matrigel
  • Collagen
  • Thrombin
  • Matrix Metalloproteinase 1