title: Anti-angiogenic action of PPARγ ligand in human umbilical vein endothelial cells is mediated by PTEN upregulation and VEGFR-2 downregulation.
abstract: Peroxisome proliferator-activated receptor γ (PPARγ) activation has anti-angiogenic and apoptotic effects in endothelial cells. Here, we investigated the mechanisms of the anti-angiogenic action of a novel PPARγ ligand, KR-62980. KR-62980 inhibited in vitro basal tube formation and in vivo neovascularization in mice induced by Matrigel containing vascular endothelial growth factor (VEGF(165), 5 ng/ml). VEGF(165)-induced cell proliferation and chemotactic migration in human umbilical vein endothelial cells (HUVECs) were also suppressed by KR-62980, in a mechanism accompanied by apoptotic cell death. KR-62980 downregulated the VEGF(165)-induced VEGFR-2 expression but increased the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression in parallel with reduced phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2), PI3K p85α, and p38 MAPK. The knockdown of PTEN expression abolished KR-62980-suppressed cell proliferation and angiogenesis. All of the effects of KR-62980 disappeared with pretreatment of bisphenol A diaglycidyl ether (BADGE), a PPARγ antagonist. In summary, KR-62980 inhibited VEGF(165)-induced angiogenesis in HUVECs by PPARγ-mediated dual mechanisms: VEGFR-2 downregulation and PTEN upregulation.
authors.affiliation: Bio-Organic Science Division, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 305-600, Korea.
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Kim
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Ahn
authors.forename: Hyae Gyeong
authors.initials: HG
authors.lastname: Cheon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001681:Biological Assay; D002196:Capillaries / Q000187:drug effects / Q000254:growth & development; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D004338:Drug Combinations; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007192:Indenes / Q000494:pharmacology*; D007797:Laminin / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D047495:PPAR gamma / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011509:Proteoglycans / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C513115:1-(methylimino-N-oxy)-6-(2-morpholinoethoxy)-3-phenyl-1H-indene-2-carboxylic acid ethyl ester; D004338:Drug Combinations; D007192:Indenes; D007797:Laminin; D008024:Ligands; D009025:Morpholines; D047495:PPAR gamma; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human