SC COBRE: SPHINGOSINE1PHOSPHATE IN EARLY BLOOD VESSEL FORMATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Sphingosine-1-phosphate (S1P) is a phosphorylated sphingolipid whose signaling is mediated by G protein-coupled receptors. Research in this project focuses on investigating the role of S1P signaling in the process of de novo formation of embryonic blood vessel, vasculogenesis. At stages preceding the formation of blood vessels (i.e., 7.5-8 dpc) in the embryo proper, yolk sac and allantois we have found that the S1P receptor S1P2 is expressed in conjunction with S1P1 and/or S1P3. Using the cultured mouse allantois explant model of blood vessel formation, we find that vasculogenesis is dependent on S1P signaling. We also have found that S1P can replace the requirement of serum for promoting vasculogenesis in cultured allantois explants. Instead, of small, poorly reticulated clusters of endothelial cells that formed under serum-free conditions, S1P promoted the formation of expansive, branched networks of capillary-like vessels. These effects could not be mimicked administration of growth factors such as VEGF or bFGF. Additionally, we have found that the ability of S1P to promote blood vessel formation is not due to it having effects on cell survival or eliciting changes in numbers of endothelial cells, angioblasts (endothelial precursor cells) or mesodermal cells (angioblast progenitor cells). Taken together, our findings indicate that S1P signaling is critically important for promoting migratory activities of angioblasts and early endothelial cells that are required for the expansion of nascent vascular networks. Research is currently focused on delineating the mechanisms by which S1P influences migratory activities of these cells during vasculogenesis. Emphasis is being placed on characterizing effects of S1P on the expression of proteins associated with cell motility (i.e., integrin adhesion receptors, their ligands and intracellular effectors of cell migration).