Sphingosine-1-phosphate (S1P) is a phosphorylated sphingolipid that mediates signaling via G-protein-coupled receptors. S1P signaling promotes an array of vascular cell behaviors important in angiogenesis and smooth muscle cell investment of nascent blood vessels. S1P signaling has not been considered to play an important role in the process of de novo formation of blood vessels, vasculogenesis. However, our recent findings indicate that vasculogenesis is dependent on S1P signaling. Specifically, S1P signaling is critical to promote migratory activities of angioblasts required for the expansion of vascular networks. A major tenet of this research project is that S1P-dependent angioblast motility has broad relevance to neovascular events in the embryo and adult. Not only can S1P-dependent angioblast motility be an important mechanism by which nascent embryonic vascular networks expand, but it may also be a critical aspect of the assembly of adult blood vessels from blood-derived endothelial cell progenitors/angioblasts. It is therefore necessary to understand the mechanisms by which S1P signaling influences angioblast motility and to establish its in vivo relevance in the context of physiological and pathological neovascular processes that involve adult vasculogenesis including tumor formation, wound healing and myocardial infarction. To address these objectives there are 3 specific aims: 1. Identify the specific S1P receptor(s) that are critical for mediating S1P signaling during vasculogenesis, 2. Characterize the involvement of integrins in S1P-induced angioblast motility, and 3. Determine the significance S1P signaling to adult vasculogenesis mediated by circulating angioblasts.
