Role of vascular endothelial growth factors in experimental colitis

• Applicant: Dr. Felix Becker
• Subject Area: Gastroenterology ; Anatomy and Physiology
• Term: from 2014 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 264371287

Human and experimental inflammatory bowel disease (IBD) are both characterized by significant increased lymphatic vessel density and redistributions in the intestinal lymphatic system. While it has been established that lymphangiogenesis is an important physiological response to inflammatory conditions (mediating immune response, limiting tissue edema and clearing immune cells), it is not well defined how lymphangiogenesis affects the course of inflammation. Previously, a variety of signaling molecules have been found to be involved in inflammation induced lymphangiogenesis. Among these, members of the vascular endothelial growth factor family (VEGF-C/D) and their receptors (VEGFR- 2/3) have been revealed as central regulators. However, the complex and often over-lapping interactions between these VEGFs and VEGFRs that affect lymphatic formation and functioning, as well as their influences on synchronization of angio- and lymphangiogenesis, remain unclear. Preliminary studies have shown that interventions in lymphangiogenic VEGF signaling pathways were able to influence the severity of murine colitis. These studies indicate that unlike angiogenesis, which exacerbates gut inflammation, enhanced lymphangiogenesis is a protective event in IBD, and may be a novel therapeutic target. Thus, we hypothesize that: Lymphangiogenic factors, liberated during intestinal inflammation, activate lymphatic proliferation via VEGF-C/D and VEGFR-3 signaling and suppress the development of intestinal edema, inflammation and tissue injury in experimental colitis. To test this hypothesis we will: determine baseline and inflammation induced changes in colonic as well as systemic: 1) VEGF-C/D levels 2) Expression of their associated VEGFR-2/3 and 3) their soluble forms (sVR2, sVR3), using the in vivo murine model of acute dextran sodium sulfate induced colitis (AIM1). Next we will use specific combinations of mutant mouse models (Chy-3, FOXC2+/-, Pax6+/-) with adenovirus-mediated gene transfers of lymphangiogenic modulators (Ad-VEGFR3-Ig, Ad-VEGF-C156S, Ad-VEGF-D) to clarify pathways related to inflammation-induced lymphangiogenesis (AIM 2). Lastly we will test the molecular and cellular mechanistic roles of VEGF-C/D and Ad-VEGFR-3-Ig on in vitro lymphatic endothelial barrier function and lymphatic smooth muscle contractility (AIM 3). The successful completion of these 3 aims will identify and discriminate the role of angiogenic and lymphangiogenic pathways in inflammation induced vascular changes in experimental colitis (Aim 1), and reveal possible mechanistic pathways involved in limiting intestinal edema and inflammatory cell accumulation (Aim 3). In particular, Aim 2 will provide novel and potentially conclusive insights into possible therapeutic applications of adenovirus-mediated modulations in VEGF signaling to shift from the established inflammation-induced angiogenesis into a more lymphangiogenic direction.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor J. Steven Alexander, Ph.D.