Sphingosine-1-phosophate signaling in vasculogenesis

描述(申请人提供)：鞘氨醇-1-磷酸(S1P)是一种磷酸化的鞘磷脂，通过G蛋白偶联受体介导信号传递。S1P信号促进一系列血管细胞行为，在新生血管的血管生成和平滑肌细胞投资中起重要作用。S1P信号尚未被认为在新生血管形成、血管生成过程中发挥重要作用。然而，我们最近的发现表明，血管生成依赖于S1P信号。具体地说，S1P信号对促进血管网络扩张所需的血管母细胞的迁移活动至关重要。这项研究的一个主要原则是，S1P依赖的血管母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依赖的血管母细胞运动不仅可能是新生胚胎血管网络扩张的重要机制，而且也可能是从血源性内皮细胞前体/血管母细胞组装成成年血管的关键方面。因此，有必要了解S1P信号影响血管母细胞运动的机制，并在包括肿瘤形成、伤口愈合和心肌梗死在内的涉及成人血管生成的生理和病理新血管过程中建立其在体内的相关性。为了解决这些目标，有三个特定的目标：1.确定在血管形成过程中介导S1P信号转导的特定S1P受体(S)，2.表征参与S1P信号转导的血管生成 整合素在S1P诱导的血管母细胞运动中的作用，以及3.确定S1P信号在循环血管母细胞介导的成人血管生成中的意义。

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.