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

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.