A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2

Nat Med. 2003 Apr;9(4):407-15. doi: 10.1038/nm846. Epub 2003 Mar 24.

Abstract

Tissue inhibitor of metalloproteinases-3 (TIMP3) is one of four members of a family of proteins that were originally classified according to their ability to inhibit matrix metalloproteinases (MMP). TIMP3, which encodes a potent angiogenesis inhibitor, is mutated in Sorsby fundus dystrophy, a macular degenerative disease with submacular choroidal neovascularization. In this study we demonstrate the ability of TIMP3 to inhibit vascular endothelial factor (VEGF)-mediated angiogenesis and identify the potential mechanism by which this occurs: TIMP3 blocks the binding of VEGF to VEGF receptor-2 and inhibits downstream signaling and angiogenesis. This property seems to be independent of its MMP-inhibitory activity, indicating a new function for this molecule.

Publication types

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

MeSH terms

  • Cell Division / drug effects
  • Cell Line
  • Endothelial Growth Factors / metabolism*
  • Endothelial Growth Factors / pharmacology
  • Endothelium / cytology
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Lymphokines / metabolism*
  • Lymphokines / pharmacology
  • Neovascularization, Pathologic / prevention & control*
  • Neuropilins / metabolism
  • Phosphorylation
  • Receptors, Vascular Endothelial Growth Factor / metabolism*
  • Recombinant Proteins / pharmacology
  • Tissue Inhibitor of Metalloproteinase-3
  • Tissue Inhibitor of Metalloproteinases / genetics
  • Tissue Inhibitor of Metalloproteinases / metabolism
  • Tissue Inhibitor of Metalloproteinases / physiology*
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Endothelial Growth Factors
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Neuropilins
  • Recombinant Proteins
  • TIMP3 protein, human
  • Tissue Inhibitor of Metalloproteinase-3
  • Tissue Inhibitor of Metalloproteinases
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Receptors, Vascular Endothelial Growth Factor