Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor.
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.
Volpert
Olga V
OV
Department of Urology, Northwestern University Medical School, Chicago, Illinois, USA. olgavolp@northwestern.edu
Zaichuk
Tetiana
T
Zhou
Wei
W
Reiher
Frank
F
Ferguson
Thomas A
TA
Stuart
P Michael
PM
Amin
Mohammad
M
Bouck
Noel P
NP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D005136:Eye Proteins; D053222:Fas Ligand Protein; D006801:Humans; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009414:Nerve Growth Factors; D011506:Proteins / Q000494:pharmacology*; D015843:Serpins / Q000494:pharmacology*; D019700:Thrombospondin 1 / Q000494:pharmacology*; D019014:fas Receptor / Q000502:physiology*; D000099174:Pigment Epithelium-Derived Factor
D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D005136:Eye Proteins; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D011506:Proteins; D015843:Serpins; D019700:Thrombospondin 1; D019014:fas Receptor; D000099174:Pigment Epithelium-Derived Factor; C505661:FASLG protein, human; C505658:Fasl protein, mouse; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse