Defining the Mechanisms of Lymphatic Vascular Growth and Function

项目摘要/摘要 淋巴管的生长是通过淋巴管生成来实现的。这些机制可以 对淋巴管生成的控制仍不完全清楚。血管内皮生长因子-C与其同源物的结合和激活 VEGFR3受体是已知的研究最充分的促淋巴管生成途径，是 淋巴管内皮细胞(LECs)的形成、迁移和增殖。的确，人类和老鼠窝藏在 VEGFR3基因的显性负突变以淋巴管发育不良为特征。相比之下，血管内皮生长因子-C 在小鼠体内过度表达会导致淋巴管过度生长和异型增生。因此，一种微妙的平衡 血管内皮生长因子C/血管内皮生长因子受体3信号对淋巴管系统的正常构型是必要的。我们有 层流切应力(LSS)是血管内皮细胞生长因子-C信号的增强子。我们还鉴定了G蛋白- 偶联受体S1P受体1(S1PR1)作为血管内皮生长因子C的拮抗剂 通过LSS增强的信令。我们将剖析LSS和S1PR1调节血管内皮生长因子的机制。 C信令。我们还将研究这种机制在健康和疾病中的意义，方法是使用 老鼠模型。

PROJECT SUMMARY/ABSTRACT Growth of lymphatic vessels from pre-existing vessels is achieved via lymphangiogenesis. The mechanisms that control lymphangiogenesis remain incompletely understood. VEGF-C binding to, and activation of, its cognate receptor VEGFR3 is the most well-studied pro-lymphangiogenic pathway known, and is necessary for the formation, migration and proliferation of lymphatic endothelial cells (LECs). Indeed, humans and mice harboring dominant negative mutations in VEGFR3 feature hypoplastic lymphatic vessels. In contrast, VEGF-C overexpression in mice results in lymphatic vessel overgrowth and dysplasia. Hence, a delicate balance of VEGF-C/VEGFR3 signaling is necessary for the proper patterning of the lymphatic vasculature. We have identified laminar shear stress (LSS) as an enhancer of VEGF-C signaling. We have also identified the G protein- coupled receptor (GPCR) sphingosine 1-phosphate (S1P) receptor 1 (S1PR1) as an antagonist of VEGF-C signaling that is enhanced by LSS. We will dissect the mechanisms by which LSS and S1PR1 regulate VEGF- C signaling. We will also investigate the significance of this mechanism during health and disease by using mouse models.