SC COBRE: SPHINGOSINE1PHOSPHATE IN EARLY BLOOD VESSEL FORMATION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。鞘氨醇-1-磷酸(S1P)是一种磷酸化的鞘磷脂，其信号转导由G蛋白偶联受体介导。本课题的研究重点是探讨S1P信号在胚胎血管从头形成、血管生成过程中的作用。在胚胎本身、卵黄囊和尿囊中血管形成之前的阶段(即7.5-8DPC)，我们发现S1P受体S1P2与S1P1和/或S1P3一起表达。利用培养的小鼠尿囊膜外植体血管形成模型，我们发现血管形成依赖于S1P信号。我们还发现，在培养的尿囊膜外植体中，S1P可以替代血清对促进血管生成的需求。相反，在无血清条件下形成的小的、网状的内皮细胞簇中，S1P促进了毛细血管样扩张的分支网络的形成。这些效应是使用生长因子如血管内皮生长因子或碱性成纤维细胞生长因子所无法比拟的。此外，我们发现S1P促进血管形成的能力并不是因为它对细胞存活有影响，也不是因为它引起内皮细胞、血管母细胞(内皮前体细胞)或中胚层细胞(血管母细胞前体细胞)数量的变化。综上所述，我们的发现表明，S1P信号对于促进新生血管网络扩张所需的血管母细胞和早期内皮细胞的迁移活动至关重要。目前的研究重点是阐明S1P在血管形成过程中影响这些细胞迁移活动的机制。重点是S1P对与细胞运动相关的蛋白质(即整合素黏附受体、它们的配体和细胞内迁移的效应物)表达的影响。

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).