gw-501516 and Ischemia

The roles of peroxisome proliferator-activated receptor (PPAR)-δ in vascular biology are mainly unknown. We investigated the effects of PPAR-δ activation on the paracrine networks between endothelial progenitor cells (EPCs) and endothelial cells (ECs)/skeletal muscle.. Treatment of EPCs with GW501516, a PPAR-δ agonist, induced specifically matrix metallo-proteinase (MMP)-9 by direct transcriptional activation. Subsequently, this increased-MMP-9 broke down insulin-like growth factor-binding protein (IGFBP)-3, resulting in IGF-1 receptor (IGF-1R) activation in surrounding target cells. Treatment of conditioned medium from GW501516-stimulated EPCs enhanced the number and functions of human umbilical vein ECs and C2C12 myoblasts via MMP-9-mediated IGF-1R activation. Systemic administration of GW501516 in mice increased MMP-9 expression in EPCs, and augmented IGFBP-3 degradation in serum. In a mouse hindlimb ischaemia model, systemic treatment of GW501516 or local transplantation of GW501516-treated EPCs induced IGF-1R phosphorylation in ECs and skeletal muscle in the ischaemic limbs, leading to augmented angiogenesis and skeletal muscle regeneration. It also enhanced wound healing with increased angiogenesis in a mouse skin punch wound model. These pro-angiogenic and muscle-regenerating effects were abolished by MMP-9 knock-out.. Our results suggest that PPAR-δ is a crucial modulator of angio-myogenesis via the paracrine effects of EPCs, and its agonist is a good candidate as a therapeutic drug for patients with peripheral vascular diseases.

Topics: Analysis of Variance; Animals; Cell Proliferation; Endothelial Cells; Heterografts; Hindlimb; Human Umbilical Vein Endothelial Cells; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Ischemia; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Mice, Nude; Monocytes; Muscle Fibers, Skeletal; Muscle, Skeletal; Neovascularization, Physiologic; Phosphorylation; PPAR delta; Receptor, IGF Type 1; Reperfusion Injury; Stem Cell Transplantation; Stem Cells; Thiazoles

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