Sphingosine-1-phosophate signaling in vasculogenesis

描述（由申请人提供）：鞘脂-1-磷酸（S1P）是一种磷酸化鞘脂，通过g蛋白偶联受体介导信号传导。S1P信号促进一系列血管细胞行为，这些行为在新生血管的血管生成和平滑肌细胞投资中很重要。S1P信号尚未被认为在血管新生形成和血管发生过程中发挥重要作用。然而，我们最近的研究结果表明血管发生依赖于S1P信号。具体来说，S1P信号对于促进血管网络扩张所需的成血管细胞的迁移活动至关重要。本研究项目的一个主要宗旨是，s1p依赖的成血管细胞运动与胚胎和成人的新生血管事件具有广泛的相关性。s1p依赖性成血管细胞运动不仅是新生胚胎血管网络扩张的重要机制，而且可能是血液来源的内皮细胞祖细胞/成血管细胞组装成人血管的关键方面。因此，有必要了解S1P信号影响成血管细胞运动的机制，并在涉及成人血管发生（包括肿瘤形成、伤口愈合和心肌梗死）的生理和病理新生血管过程中建立其体内相关性。为了实现这些目标，有三个具体目标：确定在血管发生过程中对介导S1P信号传导至关重要的特定S1P受体2。描述…的参与

DESCRIPTION (provided by applicant): 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.