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.

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.

• Authors: 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, Hyo-Soo Kim
• Journal: Circulation (Circulation) Vol. 118 Issue 10 Pg. 1021-33 (Sep 02 2008) ISSN: 1524-4539 [Electronic] United States
• PMID: 18711014 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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