PPARα Regulates Mobilization and Homing of Endothelial Progenitor Cells Through the HIF-1α/SDF-1 Pathway

PURPOSE. The mechanism for the antiangiogenic activity of peroxisome proliferator-activated receptor alpha (PPAR alpha) remains incompletely understood. Endothelial progenitor cells (EPC) are known to participate in neovascularization (NV). The purpose of this study was to investigate whether PPAR alpha regulates EPC during retinal NV. METHODS. Retinal NV was induced by oxygen-induced retinopathy (OIR). Mice with OIR were injected intraperitoneally with the PPAR alpha agonist fenofibric acid (FA) or with adenovirus expressing PPAR alpha (Ad-PPAR alpha). Flow cytometry was used to quantify circulating and retinal EPC. Serum stromal cell-derived factor 1 (SDF-1) levels were measured by ELISA. Hypoxia was induced in primary human retinal capillary endothelial cells (HRCEC) and mouse brain endothelial cells (MBEC) by CoCl2. Levels of SDF-1 and hypoxia-inducible factor 1 alpha (HIF-1 alpha) were measured by Western blotting. RESULTS. Fenofibric acid and overexpression of PPAR alpha attenuated the increase of circulating and retinal EPC, correlating with suppressed retinal NV in OIR mice at P17. The PPAR alpha knockout enhanced the OIR-induced increase of circulating and retinal EPC. Fenofibric acid decreased retinal HIF-1 alpha and SDF-1 levels as well as serum SDF-1 levels in the OIR model. In HRCEC, PPAR alpha inhibited HIF-1 alpha nuclear translocation and SDF-1 overexpression induced by hypoxia. Further, MBEC from PPAR alpha(-/-) mice showed more prominent activation of HIF-1 alpha and overexpression of SDF-1 induced by hypoxia, compared with the wild-type (WT) MBEC. PPAR alpha failed to block SDF-1 overexpression induced by a constitutively active mutant of HIF-1 alpha, suggesting that regulation of SDF-1 by PPAR alpha was through blockade of HIF-1 alpha activation. CONCLUSIONS. Peroxisome proliferator-activated receptor alpha suppresses ischemia-induced EPC mobilization and homing through inhibition of the HIF-1 alpha/SDF-1 pathway. This represents a novel molecular mechanism for PPAR alpha's antiangiogenic effects.