Defining the Mechanisms of Lymphatic Vascular Growth and Function

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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.