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



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.



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.
National Research Laboratory for Cardiovascular Stem Cell Niche, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
Jung-Kyu
JK
Han
National Research Laboratory for Cardiovascular Stem Cell Niche, Seoul National University College of Medicine, Seoul, Republic of Korea.
Back-Kyung
BK
Kim
National Research Laboratory for Cardiovascular Stem Cell Niche, Seoul National University College of Medicine, Seoul, Republic of Korea.
Joo-Yun
JY
Won
National Research Laboratory for Cardiovascular Stem Cell Niche, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
Youngchul
Y
Shin
National Research Laboratory for Cardiovascular Stem Cell Niche, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
Saet-Byeol
SB
Choi
National Research Laboratory for Cardiovascular Stem Cell Niche, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
Injoo
I
Hwang
National Research Laboratory for Cardiovascular Stem Cell Niche, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
Jeehoon
J
Kang
National Research Laboratory for Cardiovascular Stem Cell Niche, Seoul National University College of Medicine, Seoul, Republic of Korea.
Ho-Jae
HJ
Lee
National Research Laboratory for Cardiovascular Stem Cell Niche, Seoul National University College of Medicine, Seoul, Republic of Korea.
Seok-Jin
SJ
Koh
National Research Laboratory for Cardiovascular Stem Cell Niche, Seoul National University College of Medicine, Seoul, Republic of Korea.
Jaewon
J
Lee
National Research Laboratory for Cardiovascular Stem Cell Niche, Seoul National University College of Medicine, Seoul, Republic of Korea.
Jin
J
Hur
National Research Laboratory for Cardiovascular Stem Cell Niche, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
Hyun-Jai
HJ
Cho
National Research Laboratory for Cardiovascular Stem Cell Niche, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
In-Ho
IH
Chae
National Research Laboratory for Cardiovascular Stem Cell Niche, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
Byung-Hee
BH
Oh
National Research Laboratory for Cardiovascular Stem Cell Niche, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
Young-Bae
YB
Park
National Research Laboratory for Cardiovascular Stem Cell Niche, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Molecular Medicine & Biopharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea. Electronic address: hyosoo@snu.ac.kr.
Hyo-Soo
HS
Kim
D001483:Base Sequence; D001665:Binding Sites; D001792:Blood Platelets / Q000378:metabolism*; D002450:Cell Communication; D016384:Consensus Sequence; D066026:Endothelial Progenitor Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology; D018919:Neovascularization, Physiologic; D047494:PPAR delta / Q000378:metabolism*; D011485:Protein Binding; D049368:Receptors, Lysophosphatidic Acid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014945:Wound Healing
D008246:Lysophospholipids; D047494:PPAR delta; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid
Endothelial differentiation gene-2; Endothelial progentior cell; Peroxisome proliferator-activated receptor-δ; Platelet