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

Circulation. 2008 Sep 2;118(10):1021-33. doi: 10.1161/CIRCULATIONAHA.108.777169. Epub 2008 Aug 18.

Abstract

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)-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.

Methods and results: 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.

Conclusions: The results of our study suggest that PPAR-delta agonist has therapeutic vasculogenic potential for the treatment of ischemic cardiovascular diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Flow Velocity / drug effects
  • Bone Marrow / metabolism
  • Cells, Cultured
  • Corneal Neovascularization / metabolism
  • Corneal Neovascularization / pathology
  • Disease Models, Animal
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Female
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / pathology
  • Hindlimb / metabolism
  • Hindlimb / pathology
  • Humans
  • Ischemia / metabolism*
  • Ischemia / pathology
  • Ischemia / therapy
  • Male
  • Mice
  • Mice, Knockout
  • Neovascularization, Physiologic / drug effects*
  • PPAR delta / agonists*
  • PPAR delta / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Stem Cell Transplantation
  • Thiazoles / pharmacology*
  • Vascular Diseases / metabolism*
  • Vascular Diseases / pathology
  • Vascular Diseases / therapy

Substances

  • GW 501516
  • PPAR delta
  • Thiazoles
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt