VEGFR-3 blocking deteriorates inflammation with impaired lymphatic function and different changes in lymphatic vessels in acute and chronic colitis

Background: Recent studies show inflammation-associated lymphangiogenesis (IAL) induced by vascular endothelial growth factor receptor 3 (VEGFR-3) pathway has a close relationship with chronic intestinal inflammation, and antilymphatic signaling pathways may repress IAL. However, whether the biologic function of lymphatic vessel is the same in severe acute intestinal inflammation still remain unknown.

Methods: C57BL/6 mice were administered with 5% of dextran sodium sulfate (DSS) in drinking water for 7 days to establish severe acute colitis (SAC) model. Chronic colitis (CC) model was established by three cycles of 2% DSS for 5 days following water for 5 days. Mice were treated with VEGFR-3 antibody once daily in SAC group, or once every 3 days in CC group. The colon inflammation, submucosal edema, lymphatic vessel (LV) density, LV size, lymph flow, cytokines and immune cells infiltration were detected.

Results: Both acute and chronic colitis resulted in a significant aggravation of colon inflammation in anti-VEGFR-3-treated mice, compared with PBS-treated colitis mice. Meanwhile, this was accompanied with decreased lymph drainage, increased submucosal edema, inflammatory cells infiltration and cytokines levels. In acute intestinal inflammation, significantly distorted and enlarged lymphatics were found but the LV number remained unchanged; not only significantly distorted and enlarged lymphatics but reduced LV number were found in chronic colitis.

Conclusion: Blocking VEGFR-3 in acute and chronic colitis leads to deterioration of colon inflammation with impaired lymphatic function and different changes in LVs. In the therapy targeting VEGF-C/VEGFR-3 pathway for lymphangiogenesis, the phrase and severity of intestinal inflammation should be taken into account.