gw-501516 and Vascular-Diseases

Despite the therapeutic potential of endothelial progenitor cells (EPCs) in ischemic vascular diseases, their insufficient numbers limit clinical applications. Peroxisome proliferator-activated receptor (PPAR)-delta belongs to the nuclear hormone receptor superfamily, and its functions in various tissues and cells are almost unexplored, especially with respect to vascular biology.. PPAR-delta 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-delta activation with agonist (GW501516 or L-165041) increased the proliferation of human EPCs and protected them from hypoxia-induced apoptosis. In addition, PPAR-delta activation enhanced EPC functions, such as transendothelial migration, and tube formation. These actions by PPAR-delta activation in EPCs were dependent on the phosphatidylinositol 3-kinase/Akt pathway. In ischemic hindlimb of mice models, transplantation of PPAR-delta agonist-treated human or mouse EPCs enhanced blood flow recovery to ischemic limbs compared with vehicle-treated EPCs. In EPCs from PPAR-delta-knockout mice, however, treatment with PPAR-delta agonist did not enhance in vivo vasculogenic potential. Systemic administration of PPAR-delta 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.. The results of our study suggest that PPAR-delta agonist has therapeutic vasculogenic potential for the treatment of ischemic cardiovascular diseases.

Topics: Animals; Blood Flow Velocity; Bone Marrow; Cells, Cultured; Corneal Neovascularization; Disease Models, Animal; Endothelial Cells; Female; Hematopoietic Stem Cells; Hindlimb; Humans; Ischemia; Male; Mice; Mice, Knockout; Neovascularization, Physiologic; Phosphatidylinositol 3-Kinases; PPAR delta; Proto-Oncogene Proteins c-akt; Stem Cell Transplantation; Thiazoles; Vascular Diseases