Blockade of VEGF Receptor-3 Aggravates Inflammatory Bowel Disease and Lymphatic Vessel Enlargement

Background:In contrast to the prominent function of the blood vasculature in promoting tissue inflammation, the role of lymphatic vessels in inflammation has been scarcely studied in vivo. To investigate whether modulating lymphatic vessel function might affect the course of chronic inflammation, the major lymphangiogenic receptor, vascular growth factor receptor 3 (VEGFR-3, FLT4), was blocked in an established model of inflammatory bowel disease.Methods:Interleukin 10 (IL10)-deficient mice that spontaneously develop inflammatory bowel disease were treated with a blocking antibody to VEGFR-3 for 18 days, and the inflammatory changes in colon tissue and the blood and lymphatic vascularization were quantitatively analyzed.Results:We found a significant increase in the severity of colon inflammation in anti-VEGFR-3-treated mice. This was accompanied by an increased number of enlarged and tortuous lymphatic vessels and edema in colon submucosa, indicating impaired lymphatic function. In contrast, no major effects of the treatment on the blood vasculature were observed.Conclusions:These results indicate that therapies aimed at promoting lymphatic function, e.g., with prolymphangiogenic factors, such as VEGF-C, might provide a novel strategy for the treatment of inflammatory conditions, such as inflammatory bowel disease.