Interaction between platelets and endothelial progenitor cells via LPA-Edg-2 axis is augmented by PPAR-δ activation. (August 2016)

• Record Type: Journal Article
• Authors: Han, Jung-Kyu; Kim, Back-Kyung; Won, Joo-Yun; Shin, Youngchul; Choi, Saet-Byeol; Hwang, Injoo; Kang, Jeehoon; Lee, Ho-Jae; Koh, Seok-Jin; Lee, Jaewon; Hur, Jin; Cho, Hyun-Jai; Chae, In-Ho; Oh, Byung-Hee; Park, Young-Bae; Kim, Hyo-Soo
• Is Part Of: Journal of molecular and cellular cardiology. Volume 97(2016:Aug.)
• Page Start: 266
• Page End: 277
• Publication Date: 2016-08
• Subjects: ADRP Adipose differentiation-related protein -- COX Cyclooxygenase -- EBM Endothelial basal media -- EC Endothelial cells -- ECM Extracellular matrix -- Edg Endothelial differentiation gene -- EGM Endothelial growth media -- EPC Endothelial progenitor cells -- IGFBP-3 Insulin-like growth factor-1-binding protein-3 -- LPA Lysophosphatidic acid -- MMP-9 Matrix metallo-proteinase-9 -- MNCs Mononuclear cells -- PPAR-δ Peroxisome proliferator-activated receptor-δ -- PPREs PPAR response elements -- PSGL-1 P-selectin glycoprotein ligand-1 -- S1P Sphingosine 1-phosphate; Endothelial progentior cell -- Platelet -- Peroxisome proliferator-activated receptor-δ -- Endothelial differentiation gene-2; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2016.06.002
• Languages: English
• ISSNs: 0022-2828

Abstract

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. Highlights: PPAR-δ activation in late EPCs induces vasculogenesis. Edg-2 is the direct transcriptional target of PPAR-δ activation in late EPCs. Platelets interact with late EPCs via LPA-Edg-2 axis.