title: Peroxisome proliferator-activated receptor-δ activates endothelial progenitor cells to induce angio-myogenesis through matrix metallo-proteinase-9-mediated insulin-like growth factor-1 paracrine networks.
abstract: OBJECTIVE
  The roles of peroxisome proliferator-activated receptor (PPAR)-δ in vascular biology are mainly unknown. We investigated the effects of PPAR-δ activation on the paracrine networks between endothelial progenitor cells (EPCs) and endothelial cells (ECs)/skeletal muscle.
  
  
  RESULTS
  Treatment of EPCs with GW501516, a PPAR-δ agonist, induced specifically matrix metallo-proteinase (MMP)-9 by direct transcriptional activation. Subsequently, this increased-MMP-9 broke down insulin-like growth factor-binding protein (IGFBP)-3, resulting in IGF-1 receptor (IGF-1R) activation in surrounding target cells. Treatment of conditioned medium from GW501516-stimulated EPCs enhanced the number and functions of human umbilical vein ECs and C2C12 myoblasts via MMP-9-mediated IGF-1R activation. Systemic administration of GW501516 in mice increased MMP-9 expression in EPCs, and augmented IGFBP-3 degradation in serum. In a mouse hindlimb ischaemia model, systemic treatment of GW501516 or local transplantation of GW501516-treated EPCs induced IGF-1R phosphorylation in ECs and skeletal muscle in the ischaemic limbs, leading to augmented angiogenesis and skeletal muscle regeneration. It also enhanced wound healing with increased angiogenesis in a mouse skin punch wound model. These pro-angiogenic and muscle-regenerating effects were abolished by MMP-9 knock-out.
  
  
  CONCLUSIONS
  Our results suggest that PPAR-δ is a crucial modulator of angio-myogenesis via the paracrine effects of EPCs, and its agonist is a good candidate as a therapeutic drug for patients with peripheral vascular diseases.
authors.affiliation: National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jung-Kyu
authors.initials: JK
authors.lastname: Han
authors.forename: Hack-Lyoung
authors.initials: HL
authors.lastname: Kim
authors.forename: Ki-Hyun
authors.initials: KH
authors.lastname: Jeon
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Choi
authors.forename: Hyun-Sook
authors.initials: HS
authors.lastname: Lee
authors.forename: Yoo-Wook
authors.initials: YW
authors.lastname: Kwon
authors.forename: Ja-June
authors.initials: JJ
authors.lastname: Jang
authors.forename: Hyun-Jai
authors.initials: HJ
authors.lastname: Cho
authors.forename: Hyun-Jae
authors.initials: HJ
authors.lastname: Kang
authors.forename: Byung-Hee
authors.initials: BH
authors.lastname: Oh
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Park
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D064593:Heterografts; D006614:Hindlimb / Q000098:blood supply; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009000:Monocytes / Q000166:cytology; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology; D018919:Neovascularization, Physiologic / Q000502:physiology; D047494:PPAR delta / Q000819:agonists / Q000502:physiology*; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C425931:GW 501516; D018972:Insulin-Like Growth Factor Binding Protein 3; D047494:PPAR delta; D013844:Thiazoles; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D020780:Matrix Metalloproteinase 9