Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor

Nat Med. 2002 Apr;8(4):349-57. doi: 10.1038/nm0402-349.

Abstract

Natural inhibitors of angiogenesis are able to block pathological neovascularization without harming the preexisting vasculature. Here we show that two such inhibitors, thrombospondin-1 and pigment epithelium-derived factor, derive specificity for remodeling vessels from their dependence on Fas/Fas ligand (FasL)-mediated apoptosis to block angiogenesis. Both inhibitors upregulated FasL on endothelial cells. Expression of the essential partner of FasL, Fas/CD95 receptor, was low on quiescent endothelial cells and vessels but greatly enhanced by inducers of angiogenesis, thereby specifically sensitizing the stimulated cells to apoptosis by inhibitor-generated FasL. The anti-angiogenic activity of thrombospondin-1 and pigment epithelium-derived factor both in vitro and in vivo was dependent on this dual induction of Fas and FasL and the resulting apoptosis. This example of cooperation between pro- and anti-angiogenic factors in the inhibition of angiogenesis provides one explanation for the ability of inhibitors to select remodeling capillaries for destruction.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Caspase 8
  • Caspase 9
  • Caspases / physiology
  • Cells, Cultured
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / physiology*
  • Eye Proteins*
  • Fas Ligand Protein
  • Humans
  • In Vitro Techniques
  • Membrane Glycoproteins / physiology
  • Mice
  • Neovascularization, Physiologic / drug effects*
  • Nerve Growth Factors*
  • Proteins / pharmacology*
  • Serpins / pharmacology*
  • Thrombospondin 1 / pharmacology*
  • fas Receptor / physiology*

Substances

  • Eye Proteins
  • FASLG protein, human
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Membrane Glycoproteins
  • Nerve Growth Factors
  • Proteins
  • Serpins
  • Thrombospondin 1
  • fas Receptor
  • pigment epithelium-derived factor
  • CASP8 protein, human
  • CASP9 protein, human
  • Casp8 protein, mouse
  • Casp9 protein, mouse
  • Caspase 8
  • Caspase 9
  • Caspases