Pigment epithelium-derived factor exerts opposite effects on endothelial cells of different phenotypes

The anti-angiogenic activity of pigment epithelium-derived factor (PEDF) has recently been discovered on the basis of its inhibition of ischemia-induced retinal neovascularization in an animal model of retinopathy of the premature. Moreover PEDF inhibits the migration and proliferation of various endothelial cells maintained in culture with FGF₂. Since vascular endothelial growth factor (VEGF) is the main angiogenic factor expressed in hypervascularized retinas, we investigated the functions of PEDF on retinal endothelial cells whose angiogenic phenotype is controlled or not by long term exposure to VEGF as observed in human pathologies such as diabetic retinopathy. Here, we observed that PEDF exerts opposite effects on endothelial cells depending on their phenotype. We determined that when PEDF inhibits endothelial cell growth, it inhibits VEGF-induced MAPK activation. However, in endothelial cells cultured with VEGF, PEDF has a synergistic action on cell proliferation with VEGF, and this corresponds to increased MAPK activation.