Activation of the VEGFR-3 pathway by VEGF-C attenuates UVB-induced edema formation and skin inflammation by promoting lymphangiogenesis.
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.
Kajiya
Kentaro
K
Shiseido Research Center, Kanazawa-ku, Yokohama, Japan. kentaro.kajiya@to.shiseido.co.jp
Sawane
Mika
M
Huggenberger
Reto
R
Detmar
Michael
M
D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000528:radiation effects; D004487:Edema / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D007271:Injections, Intradermal; D042583:Lymphangiogenesis / Q000502:physiology* / Q000528:radiation effects; D051379:Mice; D008812:Mice, Hairless; D011855:Radiodermatitis / Q000378:metabolism / Q000517:prevention & control*; D015398:Signal Transduction / Q000502:physiology* / Q000528:radiation effects; D012871:Skin Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D014466:Ultraviolet Rays / Q000009:adverse effects*; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism*
D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3