Peroxisome Proliferator-Activated Receptor- Agonist Enhances Vasculogenesis by Regulating Endothelial Progenitor Cells Through Genomic and Nongenomic Activations of the Phosphatidylinositol 3-Kinase/Akt Pathway

Cardiovascular Center, Seoul National University Hospital, 28 Yongon-dong Chongno-gu, Seoul 110-744, Korea.
Circulation (Impact Factor: 14.43). 10/2008; 118(10):1021-33. DOI: 10.1161/CIRCULATIONAHA.108.777169
Source: PubMed


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.

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Available from: Young-Bae Park, Jan 06, 2014
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    • "The requirement for PPARβ/δ agonists for induction of pAkt suggested that the receptor might associate with protein cofactors or undergo a conformational change in order to promote the activation of the PI3K catalytic subunit. Various NHRs, including PPARβ/δ, were reported to interact with p85α and activate PI3K/Akt making this a relevant route of activation of this key signaling pathway [30], [37], [38], [39]. Furthermore, cross-talks between the PI3K/Akt and Cox-2/prostaglandin synthetic pathway, which might be highly relevant for tumor progression, might be mediated through PPARβ/δ. "
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    • "Recent studies have shown that PPARδ promotes the proliferation of several cell types. PPARδ activation has been shown to increase the proliferation and migration of endothelial progenitors as well as the number of hematopoietic stem cells in the bone marrow [34,47,48]. In addition, PPARδ has been shown to be essential for high glucose-stimulated proliferation of embryonic stem cells [35]. "
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