A protective effect of PPARa in endothelial progenitor cells through regulating metabolism

Abstract

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 a (PPARa), has shown therapeutic effects on DR in both patients and diabetic animal models. However, the function of PPARa in ECFC/CACs has not been defined. In this study, we determined the regulation of ECFC/CAC by PPARa. 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 PPARa downregulation. Activation of PPARa by fenofibrate normalized ECFC/CAC numbers and mitochondrial function in diabetes. In contrast, PPARa knockout exacerbated ECFC/CAC number decreases and mitochondrial dysfunction in diabetic mice. Primary ECFCs from PPARa2/2 mice displayed impaired proliferation, migration, and tube formation. Furthermore, PPARa2/2 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 PPARa is an endogenous regulator of ECFC/ CAC metabolism and cell fate. Diabetes-induced downregulation of PPARa contributes to ECFC/CAC deficiency and retinal vascular degeneration in DR.