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J Mol Cell Cardiol ; 97: 266-77, 2016 08.
Article in English | MEDLINE | ID: mdl-27266389

ABSTRACT

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)-δ is a nuclear receptor regulating cell metabolism. The role of PPAR-δ in late endothelial progenitor cells (EPCs) has not been fully elucidated. We aim to understand the effects of PPAR-δ activation on late EPC and to reveal the underlying mechanism. METHODS AND RESULTS: Treatment with a highly selective PPAR-δ agonist (GW501516) induced proliferation of late EPCs and enhanced their vasculogenic potential. Search for the target molecule of PPAR-δ activation revealed endothelial differentiation gene (Edg)-2. Chromatin immunoprecipitation and promoter assays demonstrated that Edg-2 gene was specifically induced by PPAR-δ through direct transcriptional activation. Lysophosphatidic acid (LPA), an Edg ligand, mimicked the pro-vasculogenic effects of GW501516 in late EPCs whereas Edg antagonist (Ki16425) blocked these effects. Edg-2 is a membrane receptor for LPA which is a major growth factor from activated platelets. Thus, the interaction between platelets and late EPCs via the LPA-Edg-2 axis was assessed. Platelet supernatant boosted the pro-vasculogenic effects of GW501516, which was reversed by antagonist to PPAR-δ (GSK0660) or Edg (Ki16425). Both of in vivo Matrigel plug model and mouse skin punch-wound model demonstrated that the combination of platelets and PPAR-δ-activated late EPCs synergistically enhanced vascular regeneration. CONCLUSIONS: There exists a synergistic interaction between human platelets and late EPCs leading to vascular regeneration. This interaction consists of LPA from platelets and its receptor Edg-2 on the surface of EPCs and can be potentiated by PPAR-δ activation in EPCs. A PPAR-δ agonist is a good candidate to achieve vasculogenesis for ischemic vascular disease.


Subject(s)
Blood Platelets/metabolism , Endothelial Progenitor Cells/metabolism , Lysophospholipids/metabolism , PPAR delta/metabolism , Receptors, Lysophosphatidic Acid/metabolism , Base Sequence , Binding Sites , Cell Communication , Consensus Sequence , Gene Expression Regulation , Humans , Lysophospholipids/pharmacology , Neovascularization, Physiologic , Protein Binding , Receptors, Lysophosphatidic Acid/chemistry , Receptors, Lysophosphatidic Acid/genetics , Transcriptional Activation , Wound Healing
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