Matrix Metalloproteinases Regulate Neovascularization by Acting as Pericellular Fibrinolysins

Cell. 1998 Oct 30;95(3):365-77. doi: 10.1016/s0092-8674(00)81768-7.

Abstract

During angiogenesis, endothelial cells penetrate fibrin barriers via undefined proteolytic mechanisms. We demonstrate that the fibrinolytic plasminogen activator (PA)-plasminogen system is not required for this process, since tissues isolated from PA- or plasminogen-deficient mice successfully neovascularize fibrin gels. By contrast, neovessel formation, in vitro and in vivo, is dependent on fibrinolytic, endothelial cell-derived matrix metalloproteinases (MMP). MMPs directly regulate this process as invasion-incompetent cells penetrate fibrin barriers when transfected with the most potent fibrinolytic metalloproteinase identified in endothelium, membrane type-1 MMP (MT1-MMP). Membrane display of MT1-MMP is required, as invasion-incompetent cells expressing a fibrinolytically active, transmembrane-deleted form of MT1-MMP remain noninvasive. These observations identify a PA-independent fibrinolytic pathway wherein tethered MMPs function as pericellular fibrinolysins during the neovascularization process.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aorta / cytology
  • Cells, Cultured
  • Endothelial Growth Factors / pharmacology
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / enzymology
  • Fibrin / drug effects
  • Fibrin / metabolism*
  • Fibrinolysin / metabolism
  • Fibrinolysis
  • Fibroblasts
  • Hepatocyte Growth Factor / pharmacology
  • Humans
  • Lymphokines / pharmacology
  • Matrix Metalloproteinase 14
  • Matrix Metalloproteinase 3 / genetics
  • Matrix Metalloproteinase 3 / pharmacology
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / metabolism*
  • Mice
  • Muscle, Smooth
  • Neovascularization, Physiologic*
  • Plasminogen / deficiency
  • Plasminogen / metabolism
  • Plasminogen Activators / metabolism
  • Rats
  • Transforming Growth Factor alpha / pharmacology
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Endothelial Growth Factors
  • Lymphokines
  • Mmp14 protein, mouse
  • Transforming Growth Factor alpha
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Hepatocyte Growth Factor
  • Fibrin
  • Plasminogen
  • Plasminogen Activators
  • Fibrinolysin
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 14