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

Invest Ophthalmol Vis Sci. 2014 May 20;55(6):3820-32. doi: 10.1167/iovs.13-13396.


Purpose: 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.

Keywords: PPARα; endothelial progenitor cells; neovascularization; oxygen-induced retinopathy; retina.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Cerebrovascular Circulation
  • Chemokine CXCL12 / metabolism*
  • Disease Models, Animal
  • Endothelium, Vascular / metabolism*
  • Fenofibrate / analogs & derivatives
  • Fenofibrate / pharmacology
  • Flow Cytometry
  • Fluorescein Angiography
  • Gene Expression / physiology
  • Hematopoietic Stem Cell Mobilization*
  • Humans
  • Hypolipidemic Agents / pharmacology
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxygen / toxicity
  • PPAR alpha / agonists
  • PPAR alpha / physiology*
  • Real-Time Polymerase Chain Reaction
  • Retinal Neovascularization / pathology
  • Retinal Neovascularization / prevention & control
  • Retinal Vessels / cytology
  • Stem Cells / metabolism*


  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Hif1a protein, mouse
  • Hypolipidemic Agents
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • PPAR alpha
  • fenofibric acid
  • Oxygen
  • Fenofibrate