• Zhongxiao Wang, Elizabeth Moran, Lexi Ding, Rui Cheng, Xun Xu, and Jian-xing Ma.
• Department of Ophthalmology, Shanghai First People's Hospital Affiliated with Shanghai Jiaotong University, Shanghai, China Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
• Invest. Ophthalmol. Vis. Sci. 2014 May 20; 55 (6): 3820-32.

PurposeThe mechanism for the antiangiogenic activity of peroxisome proliferator-activated receptor alpha (PPARα) remains incompletely understood. Endothelial progenitor cells (EPC) are known to participate in neovascularization (NV). The purpose of this study was to investigate whether PPARα regulates EPC during retinal NV.MethodsRetinal NV was induced by oxygen-induced retinopathy (OIR). Mice with OIR were injected intraperitoneally with the PPARα agonist fenofibric acid (FA) or with adenovirus expressing PPARα (Ad-PPARα). 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-1α) were measured by Western blotting.ResultsFenofibric acid and overexpression of PPARα attenuated the increase of circulating and retinal EPC, correlating with suppressed retinal NV in OIR mice at P17. The PPARα knockout enhanced the OIR-induced increase of circulating and retinal EPC. Fenofibric acid decreased retinal HIF-1α and SDF-1 levels as well as serum SDF-1 levels in the OIR model. In HRCEC, PPARα inhibited HIF-1α nuclear translocation and SDF-1 overexpression induced by hypoxia. Further, MBEC from PPARα(-/-) mice showed more prominent activation of HIF-1α and overexpression of SDF-1 induced by hypoxia, compared with the wild-type (WT) MBEC. PPARα failed to block SDF-1 overexpression induced by a constitutively active mutant of HIF-1α, suggesting that regulation of SDF-1 by PPARα was through blockade of HIF-1α activation.ConclusionsPeroxisome proliferator-activated receptor alpha suppresses ischemia-induced EPC mobilization and homing through inhibition of the HIF-1α/SDF-1 pathway. This represents a novel molecular mechanism for PPARα's antiangiogenic effects.Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

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