Promoting inflammatory lymphangiogenesis by vascular endothelial growth factor-C (VEGF-C) aggravated intestinal inflammation in mice with experimental acute colitis

Abstract

Angiogenesis and lymphangiogenesis are thought to play a role in the pathogenesis of inflammatory bowel diseases (IBD). However, it is not understood if inflammatory lymphangiogenesis is a pathological consequence or a productive attempt to resolve the inflammation. This study investigated the effect of lymphangiogenesis on intestinal inflammation by overexpressing a lymphangiogenesis factor, vascular endothelial growth factor-C (VEGF-C), in a mouse model of acute colitis. Forty eight-week-old female C57BL/6 mice were treated with recombinant adenovirus overexpressing VEGF-C or with recombinant VEGF-C156S protein. Acute colitis was then established by exposing the mice to 5% dextran sodium sulfate (DSS) for 7 days. Mice were evaluated for disease activity index (DAI), colonic inflammatory changes, colon edema, microvessel density, lymphatic vessel density (LVD), and VEGFR-3mRNA expression in colon tissue. When acute colitis was induced in mice overexpressing VEGF-C, there was a significant increase in colonic epithelial damage, inflammatory edema, microvessel density, and neutrophil infiltration compared to control mice. These mice also exhibited increased lymphatic vessel density (73.0±3.9 vs 38.2±1.9, P<0.001) and lymphatic vessel size (1974.6±104.3 vs 1639.0±91.5, P<0.001) compared to control mice. Additionally, the expression of VEGFR-3 mRNA was significantly upregulated in VEGF-C156S mice compared to DSS-treated mice after induction of colitis (42.0±1.4 vs 3.5±0.4, P<0.001). Stimulation of lymphangiogenesis by VEGF-C during acute colitis promoted inflammatory lymphangiogenesis in the colon and aggravated intestinal inflammation. Inflammatory lymphangiogenesis may have pleiotropic effects at different stages of IBD.

Lymphatic deletion of calcitonin receptor–like receptor exacerbates intestinal inflammation

“…did not promote disease resolution in mice with acute experimental colitis (18). Collectively, these results suggest either that lymphatic insufficiency may be causative of IBDs or that incorrect lymphatic expansion and function can exacerbate the disease phenotype.…”

Acute small intestinal inflammation results in persistent lymphatic alterations

“…11 and 36). Studies of IBD-affected intestine and experimentally inflamed colon have highlighted mesenteric and intestinal lymphatic abnormalities, including submucosal edema, lymphatic vessel dilation, lymphadenopathy, lymphatic obstruction, and lymphangiogenesis, the proliferation of new lymphatic vessels (2,3,6,7,15,31,32,50,70,71). Although these studies have mostly focused on intestinal lymphatic abnormalities, the role of the mesenteric lymphatics has more recently also been appreciated.…”

Exploiting lymphatic vessels for immunomodulation: Rationale, opportunities, and challenges

“…The alteration of lymphatic drainage in humans has been observed through recently published dye injection studies, where dye was injected into resected regions of the gastrointestinal tract of IBD patients in areas with or without ulcers or inflammation [103]. These studies found that collecting lymphatics associated with creeping fat and that drain to the mesenteric LNs are remodeled by B cells and innate lymphoid cells invading the lymphatic wall, and that the lymphoid aggregates (also called tertiary lymphoid organs) alter Ag and immune cell trafficking to the mesenteric LN and thus contribute to disease progression [104]. In mouse models, there is not a clear consensus on how lymphangiogenesis affects IBD, and to what extent it is protective vs. pathological.…”

“…In mouse models, there is not a clear consensus on how lymphangiogenesis affects IBD, and to what extent it is protective vs. pathological. In a mouse model of colitis induced by dextran sulfate sodium (DSS), Wang et al found that VEGF-C overexpression and associated increased lymphatic vessel density worsened the disease [104], which could be interpreted as lymphangiogenesis contributing to the pathogenesis of IBD. On the other hand, inflammatory lymphangiogenesis already occurs in DSS-induced colitis, and thus these experiments can only demonstrate that super(patho)physiological levels of VEGF-C, in excess of what is produced in the inflamed environment, exacerbates inflammation and tissue damage resulting from DSS.…”