Role of vascular endothelial growth factors in experimental colitis

血管内皮生长因子在实验性结肠炎中的作用

• 批准号: 264371287
• 负责人: Dr. Felix Becker
• 金额: --
• 依托单位: Department of Cellular and Molecular Physiology (aufgelöst)
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/264371287?language=en
• 关键词: Role; vascular; endothelial; growth; factors

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.

人和实验性炎症性肠病（IBD）的特征都是淋巴血管密度显著增加和肠淋巴系统的重新分布。虽然已经确定淋巴管生成是对炎症条件的重要生理反应（介导免疫反应，限制组织水肿和清除免疫细胞），但淋巴管生成如何影响炎症过程尚不清楚。此前，已经发现多种信号分子参与炎症诱导的淋巴管生成。其中，血管内皮生长因子家族成员（VEGF-C/D）及其受体（VEGFR- 2/3）已被发现是中枢调节因子。然而，这些vegf和vegfr之间影响淋巴形成和功能的复杂且经常重叠的相互作用，以及它们对血管和淋巴管生成同步的影响，仍不清楚。初步研究表明，干预淋巴管生成的VEGF信号通路能够影响小鼠结肠炎的严重程度。这些研究表明，不同于血管生成会加剧肠道炎症，增强淋巴管生成是IBD的保护事件，可能是一个新的治疗靶点。因此，我们假设：肠道炎症过程中释放的淋巴管生成因子通过VEGF-C/D和VEGFR-3信号激活淋巴细胞增殖，抑制实验性结肠炎肠道水肿、炎症和组织损伤的发生。为了验证这一假设，我们将：确定基线和炎症诱导的结肠和全身变化：1)VEGF-C/D水平；2)相关VEGFR-2/3的表达；3)它们的可溶性形式（sVR2, sVR3），使用急性葡聚糖硫酸钠诱导结肠炎（AIM1）的体内小鼠模型。接下来，我们将使用突变小鼠模型（hy-3, FOXC2+/-, Pax6+/-）与腺病毒介导的淋巴管生成调节剂（Ad-VEGFR3-Ig, Ad-VEGF-C156S, Ad-VEGF-D）的特定组合来阐明炎症诱导淋巴管生成的相关途径（AIM 2）。最后，我们将测试VEGF-C/D和Ad-VEGFR-3-Ig在体外淋巴内皮屏障功能和淋巴平滑肌收缩性（AIM 3）中的分子和细胞机制作用。成功完成这3个目标将识别和区分血管生成和淋巴管生成途径在实验性结肠炎炎症诱导的血管变化中的作用（目的1），并揭示可能参与限制肠道水肿和炎症细胞积聚的机制途径（目的3）。特别是，Aim 2将为腺病毒介导的VEGF信号调节的可能治疗应用提供新的和潜在的结论性见解，从既定的炎症诱导的血管生成转向更淋巴管生成的方向。