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

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.

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Figure 1: The roles of Fas and FasL induced by TSP1 and PEDF in apoptosis of cultured endothelial cells.
Figure 2: TSP1 and PEDF increased FasL mRNA and surface protein in endothelial cells.
Figure 3: Several angiogenic stimuli enhanced endothelial cell apoptosis by inhibitory TSP1, and increased surface Fas.
Figure 4: Expression of Fas receptor on newly forming capillaries induced in vivo.
Figure 5: Inactivation of Fas or FasL blocked the anti-angiogenic activity of TSP1 and PEDF in vitro and in vivo.

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Acknowledgements

We thank M. Wu for technical help. This work was supported by NIH grants RO1 CA52750 and CA64239 (N.B.), American Heart Association grant SDG0030023N, American Cancer Society grant RSG-01-099-01-CSM and NIH RO1 68003-01 (O.V.), Foundation for Fighting Blindness grants EY12826 (T.A.F.) and EY12707 (P.M.S.).

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Correspondence to Olga V. Volpert.

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Volpert, O., Zaichuk, T., Zhou, W. et al. Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium–derived factor. Nat Med 8, 349–357 (2002). https://doi.org/10.1038/nm0402-349

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