PPARα regulates mobilization and homing of endothelial progenitor cells through the HIF-1α/SDF-1 pathway.
OBJECTIVE
The 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.


METHODS
Retinal 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.


RESULTS
Fenofibric 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.


CONCLUSIONS
Peroxisome 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.
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.
Zhongxiao
Z
Wang
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
Elizabeth
E
Moran
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China.
Lexi
L
Ding
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
Rui
R
Cheng
Department of Ophthalmology, Shanghai First People's Hospital Affiliated with Shanghai Jiaotong University, Shanghai, China.
Xun
X
Xu
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
Jian-xing
JX
Ma
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation; D054377:Chemokine CXCL12 / Q000378:metabolism*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism*; D011345:Fenofibrate / Q000031:analogs & derivatives / Q000494:pharmacology; D005434:Flow Cytometry; D005451:Fluorescein Angiography; D015870:Gene Expression / Q000502:physiology; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen / Q000633:toxicity; D047493:PPAR alpha / Q000819:agonists / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D015861:Retinal Neovascularization / Q000473:pathology / Q000517:prevention & control; D012171:Retinal Vessels / Q000166:cytology; D013234:Stem Cells / Q000378:metabolism*
D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; C497443:Hif1a protein, mouse; D000960:Hypolipidemic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047493:PPAR alpha; C006012:fenofibric acid; D010100:Oxygen; D011345:Fenofibrate
PPARα; endothelial progenitor cells; neovascularization; oxygen-induced retinopathy; retina