Peroxisome proliferator-activated receptor-δ agonist enhances vasculogenesis by regulating endothelial progenitor cells through genomic and nongenomic activations of the phosphatidylinositol 3-kinase/Akt pathway

Background - Despite the therapeutic potential of endothelial progenitor cells (EPCs) in ischemic vascular diseases, their insufficient numbers limit clinical applications. Peroxisome proliferator-activated receptor (PPAR)-δ belongs to the nuclear hormone receptor superfamily, and its functions in various tissues and cells are almost unexplored, especially with respect to vascular biology. Methods and Results - PPAR-δ activation in EPCs phosphorylated Akt, and this phosphorylation was mediated not only by genomic but also by nongenomic pathways through interaction with the regulatory subunit of phosphatidylinositol 3-kinase. PPAR-δ activation with agonist (GW501516 or L-165041) increased the proliferation of human EPCs and protected them from hypoxia-induced apoptosis. In addition, PPAR-δ activation enhanced EPC functions, such as transendothelial migration, and tube formation. These actions by PPAR-δ activation in EPCs were dependent on the phosphatidylinositol 3-kinase/Akt pathway. In ischemic hindlimb of mice models, transplantation of PPAR-δ agonist-treated human or mouse EPCs enhanced blood flow recovery to ischemic limbs compared with vehicle-treated EPCs. In EPCs from PPAR-δ-knockout mice, however, treatment with PPAR-δ agonist did not enhance in vivo vasculogenic potential. Systemic administration of PPAR-δ agonist increased hematopoietic stem cells in bone marrow and EPCs in peripheral blood, leading to improved vasculogenesis with incorporation of bone marrow-derived cells to new vessels in a corneal neovascularization model and limb salvage with better blood flow in an ischemic hindlimb model. Conclusions - The results of our study suggest that PPAR-δ agonist has therapeutic vasculogenic potential for the treatment of ischemic cardiovascular diseases.