The VEGF-C/VEGFR3 signaling pathway contributes to resolving chronic skin inflammation by activating lymphatic vessel function

Asami Hagura, Jun Asai, Kazuichi Maruyama, Hideya Takenaka, Shigeru Kinoshita, Norito Katoh

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)


Background: The functions of lymphatic vessels are to drain the protein-rich lymph from the extracellular space, to maintain normal tissue pressure, and to mediate the immune response, particularly in inflammatory conditions. Objective: To evaluate the function of the vascular endothelial growth factor (VEGF)-C/VEGF receptor (VEGFR)-3 signaling pathway in chronic skin inflammation. Methods: We used adenovirus-mediated VEGF-C or VEGFR3-immunoglobulin (Ig) production and investigated the effects of VEGF-C/VEGFR3 signaling on the resolution of inflammation using the experimental chronic contact hypersensitivity (CHS) reaction mouse model. Results: VEGF-C gene transfer promoted significant reduction of ear swelling and ear weight in CHS reaction-induced skin inflammation. Although, there was no significant difference in the number of lymphatic vessels, the number of infiltrating CD11b-positive inflammatory cells was significantly reduced in the VEGF-C group, which suggested that VEGF-C upregulated the drainage of interstitial fluid and inflammatory cells via lymphatic vessels. Furthermore, blockade of VEGFR3 expression resulted in a significant delay in the recovery from CHS reaction-induced skin inflammation. Lymphatic vessel size was enlarged and a significant increase of infiltrating CD11b inflammatory cells was observed in mice with VEGFR3-Ig gene transfer compared to control mice. These results suggested that blockade of VEGFR3 inhibited the drainage function of the lymphatic system. Conclusion: This study provides evidence that VEGF-C/VEGFR3 signaling plays an important role in the resolution of skin inflammation; the regulation of lymphatic function may have a great therapeutic potential in inflammatory skin diseases.

Original languageEnglish
Pages (from-to)135-141
Number of pages7
JournalJournal of dermatological science
Issue number2
Publication statusPublished - 2014 Feb


  • Chronic delayed-type hypersensitivity reaction
  • Lymphatic vessels
  • VEGF-C
  • VEGFR3

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology


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