A Protective Effect of PPARα in Endothelial Progenitor Cells Through Regulating Metabolism

Deficiency of endothelial progenitor cells, including endothelial colony-forming cells (ECFCs) and circulating angiogenic cells (CACs), plays an important role in retinal vascular degeneration in diabetic retinopathy (DR). Fenofibrate, an agonist of peroxisome proliferator-activated receptor alpha (PPAR alpha), has shown therapeutic effects on DR in both patients and diabetic animal models. However, the function of PPAR alpha in ECFC/CACs has not been defined. In this study, we determined the regulation of ECFC/CAC by PPAR alpha. As shown by flow cytometry and Seahorse analysis, ECFC/CAC numbers and mitochondrial function were decreased in the bone marrow, circulation, and retina of db/db mice, correlating with PPAR alpha downregulation. Activation of PPAR alpha by fenofibrate normalized ECFC/CAC numbers and mitochondrial function in diabetes. In contrast, PPAR alpha knockout exacerbated ECFC/CAC number decreases and mitochondrial dysfunction in diabetic mice. Primary ECFCs from PPAR alpha(-/-) mice displayed impaired proliferation, migration, and tube formation. Furthermore, PPAR alpha(-/-) ECFCs showed reduced mitochondrial oxidation and glycolysis compared with wild type, correlating with decreases of Akt phosphorylation and expression of its downstream genes regulating ECFC fate and metabolism. These findings suggest that PPAR alpha is an endogenous regulator of ECFC/CAC metabolism and cell fate. Diabetes-induced downregulation of PPAR alpha contributes to ECFC/CAC deficiency and retinal vascular degeneration in DR.