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

Hyo Soo Kim, Jung Kyu Han, Hyun Sook Lee, Han Mo Yang, Jin Hur, Soo In Jun, Ju Young Kim, Chung Hyun Cho, Gou Young Koh, Jeffrey M. Peters, Kyung Woo Park, Hyun Jai Cho, Hae Young Lee, Hyun Jae Kang, Byung Hee Oh, Young Bae Park

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

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)-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.

Original languageEnglish (US)
Pages (from-to)1021-1033
Number of pages13
JournalCirculation
Volume118
Issue number10
DOIs
StatePublished - Sep 2 2008

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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