Activation of the VEGFR-3 pathway by VEGF-C attenuates UVB-induced edema formation and skin inflammation by promoting lymphangiogenesis

J Invest Dermatol. 2009 May;129(5):1292-8. doi: 10.1038/jid.2008.351. Epub 2008 Nov 13.

Abstract

We have previously demonstrated that UVB irradiation resulted in impaired function of cutaneous lymphatic vessels, suggesting a crucial role of lymphatic function in the mediation of UVB-induced inflammation. Nonetheless, the molecular mechanisms of lymphatic involvement in inflammation have remained unclear. Here, we show that vascular endothelial growth factor (VEGF)-C expression is downregulated after UVB irradiation, associated with enlargement of lymphatic vessels and with an increase of macrophage infiltration in the dermis. To determine whether activation of VEGF-C/VEGFR-3 signaling might reduce UVB-induced inflammation, mice were exposed to a single dose of UVB irradiation together with intradermal injection of mutant VEGF-C (Cys156Ser), which specifically binds to VEGFR-3 on lymphatic endothelium. We found that the activation of VEGFR-3 attenuated UVB-induced edema formation, associated with a decreased number of CD11b-positive macrophages. Moreover, mutant VEGF-C injection inhibited UVB-induced enlargement of lymphatic vessels and also induced the proliferation of lymphatic endothelial cells. In contrast, treatment with mutant VEGF-C had no effect on blood vessel size or number. These results demonstrate that UVB-induced lymphatic impairment is mediated by downregulation of VEGF-C expression and that the activation of the VEGF-C/VEGFR-3 pathway might represent a feasible target for the prevention of UVB-induced inflammation by promoting lymphangiogenesis.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Down-Regulation / radiation effects
  • Edema / etiology
  • Edema / metabolism
  • Edema / prevention & control*
  • Female
  • Injections, Intradermal
  • Lymphangiogenesis / physiology*
  • Lymphangiogenesis / radiation effects
  • Mice
  • Mice, Hairless
  • Radiodermatitis / metabolism
  • Radiodermatitis / prevention & control*
  • Signal Transduction / physiology*
  • Signal Transduction / radiation effects
  • Skin Diseases / etiology
  • Skin Diseases / metabolism
  • Skin Diseases / prevention & control
  • Ultraviolet Rays / adverse effects*
  • Vascular Endothelial Growth Factor C / metabolism*
  • Vascular Endothelial Growth Factor Receptor-3 / genetics
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism*

Substances

  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor Receptor-3