title: Vascular endothelial growth factor-D mediates fibrogenic response in myofibroblasts.
abstract: Vascular endothelial growth factor (VEGF)-D is a crucial mediator of angiogenesis. Following myocardial infarction (MI), cardiac VEGF-D and VEGF receptor (VEGFR)-3 are significantly upregulated. In addition to endothelial cells, myofibroblasts at the site of MI highly express VEGFR-3, implicating the involvement of VEGF-D in cardiac fibrogenesis that promotes repair and remodeling. The aim of the current study was to further explore the critical role of VEGF-D in fibrogenic response in myofibroblasts. Myofibroblast proliferation, migration, collagen synthesis, and degradation were investigated in cultured cardiac myofibroblasts subjected to VEGF-D with/without VEGFR antagonist or ERK inhibitor. Vehicle-treated cells served as controls. Myofibroblast proliferation and migration were detected by BrdU assay and Boyden Chamber method, respectively. Expression of type I collagen, metalloproteinase (MMP)-2/-9, tissue inhibitor of MMP (TIMP)-1/-2, and ERK phosphorylation were evaluated by Western blot analyses. Our results revealed that compared to controls, (1) VEGF-D significantly increased myofibroblast proliferation and migration; (2) VEGF-D significantly upregulated type I collagen synthesis in a dose- and time-dependent manner; (3) VEGFR antagonist abolished VEGF-D-induced myofibroblast proliferation and type I collagen release; (4) VEGF-D stimulated MMP-2/-9 and TIMP-1/-2 synthesis; (5) VEGF-D activated ERK phosphorylation; and (6) ERK inhibitor abolished VEGF-D-induced myofibroblast proliferation and type I collagen synthesis. Our in vitro studies have demonstrated that VEGF-D serves as a crucial profibrogenic mediator by stimulating myofibroblast growth, migration and collagen synthesis. Further studies are underway to determine the role of VEGF-D in fibrous tissue formation during cardiac repair following MI.
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, 956 Court Ave, Room B324, Memphis, TN, 38163, USA.
authors.forename: Tieqiang
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, 956 Court Ave, Room B324, Memphis, TN, 38163, USA.
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, 956 Court Ave, Room B324, Memphis, TN, 38163, USA.
authors.forename: Weixin
authors.initials: W
authors.lastname: Meng
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, 956 Court Ave, Room B324, Memphis, TN, 38163, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, 956 Court Ave, Room B324, Memphis, TN, 38163, USA.
authors.forename: Yuanjian
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, 956 Court Ave, Room B324, Memphis, TN, 38163, USA.
authors.forename: Syamal K
authors.initials: SK
authors.lastname: Bhattacharya
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, 956 Court Ave, Room B324, Memphis, TN, 38163, USA. yasun@uthsc.edu.
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology; D008297:Male; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism*
chemical_list: C441602:3-(4-dimethylamino-naphthalen-1-ylmethylene)-1,3-dihydro-indol-2-one; D002070:Butadienes; D024042:Collagen Type I; D007211:Indoles; C499138:N-(2,4-difluorophenyl)-N'-(4-((6,7-dimethoxy-4-quinolyl)oxy)-2-fluorophenyl)urea; D009281:Naphthalenes; D009570:Nitriles; D010671:Phenylurea Compounds; D011804:Quinolines; C113580:U 0126; C579459:VEGFD protein, human; D042643:Vascular Endothelial Growth Factor D; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Collagen degradation; Collagen synthesis; ERK phosphorylation; Myofibroblasts; VEGF-D