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Antiangiogenic Signaling by PEDF: The Role of Fas Death Cascade

Olga V. Volpert

The vasculature of normal mammalian eye remains quiescent, due in part to the inhibitors of angiogenesis that prevent the vessels from invading the cornea and vitreous fluid. PEDF was identified as one of the major inhibitors of angiogenesis in the normal eye of human and mouse, regulated posttranscriptionally by oxygen content. Low molar ratios between inhibitory PEDF and proangiogenic vascular endothelial growth factor (VEGF) in the eyes of diabetic patients at risk of developing proliferative retinopathy were significantly lower. Moreover, PEDF/VEGF ratios were predictive of the poor outcome and progression of eye disease, whereas VEGF levels alone were not. Acute macular degeneration, a condition that frequently leads to blindness in the aging population, was associated with more than an eightfold decrease in PEDF in vitreous fluid compared with age-matched controls. Both observations suggest that the loss of PEDF creates a permissive environment for pathological neovascularization in human eye disease. While studying the molecular mechanisms behind the antiangiogenic activity of PEDF, we found that this inhibitor blocks angiogenesis via programmed cell death by inducing a well-known secondary receptor-mediated signaling death cascade that involves CD95/Fas and its natural ligand in the activated endothelium. Paradoxically, the display of necessary Fas receptor was maintained in the activated endothelium by angiogenic stimuli.