Molecular and Cellular Biochemistry

, Volume 413, Issue 1–2, pp 127–135 | Cite as

Vascular endothelial growth factor-D mediates fibrogenic response in myofibroblasts

  • Tieqiang Zhao
  • Wenyuan Zhao
  • Weixin Meng
  • Chang Liu
  • Yuanjian Chen
  • Syamal K. Bhattacharya
  • Yao Sun


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.


Myofibroblasts VEGF-D Collagen synthesis Collagen degradation ERK phosphorylation 



This work was supported by NIH Heart, Blood, and Lung Institute (1RO1-HL096503, Yao Sun).

Compliance with ethical standards

Conflict of interest

None declared.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Tieqiang Zhao
    • 1
  • Wenyuan Zhao
    • 1
  • Weixin Meng
    • 1
  • Chang Liu
    • 1
  • Yuanjian Chen
    • 1
  • Syamal K. Bhattacharya
    • 1
  • Yao Sun
    • 1
  1. 1.Division of Cardiovascular Diseases, Department of MedicineUniversity of Tennessee Health Science CenterMemphisUSA

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