Molecular Medicine

, Volume 20, Issue 1, pp 120–134 | Cite as

Transforming Growth Factor-β1 Downregulates Vascular Endothelial Growth Factor-D Expression in Human Lung Fibroblasts via the Jun NH2-Terminal Kinase Signaling Pathway

  • Ye Cui
  • Juan C. Osorio
  • Cristobal Risquez
  • Hao Wang
  • Ying Shi
  • Bernadette R. Gochuico
  • Danielle Morse
  • Ivan O. Rosas
  • Souheil El-Chemaly
Research Article


Vascular endothelial growth factor (VEGF)-D, a member of the VEGF family, induces both angiogenesis and lymphangiogenesis by activating VEGF receptor-2 (VEGFR-2) and VEGFR-3 on the surface of endothelial cells. Transforming growth factor (TGF)-β1 has been shown to stimulate VEGF-A expression in human lung fibroblast via the Smad3 signaling pathway and to induce VEGF-C in human proximal tubular epithelial cells. However, the effects of TGF-β1 on VEGF-D regulation are unknown. To investigate the regulation of VEGF-D, human lung fibroblasts were studied under pro-fibrotic conditions in vitro and in idiopathic pulmonary fibrosis (IPF) lung tissue. We demonstrate that TGF-β1 downregulates VEGF-D expression in a dose- and time-dependent manner in human lung fibroblasts. This TGF-β1 effect can be abolished by inhibitors of TGF-β type I receptor kinase and Jun NH2-terminal kinase (JNK), but not by Smad3 knockdown. In addition, VEGF-D knockdown in human lung fibroblasts induces G1/S transition and promotes cell proliferation. Importantly, VEGF-D protein expression is decreased in lung homogenates from IPF patients compared with control lung. In IPF lung sections, fibroblastic foci show very weak VEGF-D immunoreactivity, whereas VEGF-D is abundantly expressed within alveolar interstitial cells in control lung. Taken together, our data identify a novel mechanism for downstream signal transduction induced by TGF-β1 in lung fibroblasts, through which they may mediate tissue remodeling in IPF.



This work was supported by National Institutes of Health Grant K22HL092223-A1 (to S El-Chemaly) and in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health.

The authors would like to thank Mark Perrella and Gustavo Pacheco-Rodriguez for helpful discussions and advice.

Supplementary material

10020_2014_2001120_MOESM1_ESM.pdf (701 kb)
Supplementary material, approximately 700 KB.


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Authors and Affiliations

  • Ye Cui
    • 1
  • Juan C. Osorio
    • 1
  • Cristobal Risquez
    • 1
  • Hao Wang
    • 1
  • Ying Shi
    • 1
  • Bernadette R. Gochuico
    • 2
  • Danielle Morse
    • 1
  • Ivan O. Rosas
    • 1
  • Souheil El-Chemaly
    • 1
  1. 1.Division of Pulmonary and Critical Care MedicineBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  2. 2.Medical Genetics BranchNational Human Genome Research Institute, National Institutes of HealthBethesdaUSA

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