Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, New York 10021, USA.
J Biol Chem. 2013 Jan 25;288(4):2143-56. doi: 10.1074/jbc.M112.427344. Epub 2012 Dec 10.
Sphingosine 1-phosphate (S1P) binds G-protein-coupled receptors (S1P(1-5)) to regulate a multitude of physiological effects, especially those in the vascular and immune systems. S1P receptors in the vascular system have been characterized primarily in mammals. Here, we report that the S1P receptors and metabolic enzymes are conserved in the genome of zebrafish Danio rerio. Bioinformatic analysis identified seven S1P receptor-like sequences in the zebrafish genome, including duplicated orthologs of receptors 3 and 5. Sphingolipidomic analysis detected erythrocyte and plasma S1P as well as high plasma ceramides and sphingosine. Morpholino-mediated knockdown of s1pr1 causes global and pericardial edema, loss of blood circulation, and vascular defects characterized by both reduced vascularization in intersegmental vessels, decreased proliferation of intersegmental and axial vessels, and hypersprouting in the caudal vein plexus. The s1pr2 gene was previously characterized as a regulator of cell migration and heart development, but its role in angiogenesis is not known. However, when expression of both s1pr1 and s1pr2 is suppressed, severely reduced vascular development of the intersegmental vessels was observed with doses of the s1pr1 morpholino that alone did not cause any discernible vascular defects, suggesting that s1pr1 and s1pr2 function cooperatively to regulate vascular development in zebrafish. Similarly, the S1P transporter, spns2, also cooperated with s1pr1. We propose that extracellular S1P acts through vascular S1P receptors to regulate vascular development.
鞘氨醇 1-磷酸（S1P）通过与 G 蛋白偶联受体（S1P（1-5））结合来调节多种生理效应，特别是在血管和免疫系统中的效应。血管系统中的 S1P 受体在哺乳动物中得到了较好的描述。在这里，我们报告说 S1P 受体和代谢酶在斑马鱼 Danio rerio 的基因组中是保守的。生物信息学分析在斑马鱼基因组中鉴定出了 7 种 S1P 受体样序列，包括受体 3 和 5 的重复直系同源物。鞘脂组学分析检测到红细胞和血浆 S1P 以及高血浆神经酰胺和鞘氨醇。S1PR1 的 Morpholino 介导敲低导致全身性和心包水肿、血液循环丧失以及血管缺陷，其特征为节间血管的血管生成减少、节间和轴向血管的增殖减少以及尾静脉丛的过度发芽。S1PR2 基因以前被描述为细胞迁移和心脏发育的调节剂，但它在血管生成中的作用尚不清楚。然而，当同时抑制 s1pr1 和 s1pr2 的表达时，与单独使用 s1pr1 morpholino 引起的任何可识别的血管缺陷相比，节间血管的血管发育严重减少，这表明 s1pr1 和 s1pr2 协同作用以调节斑马鱼的血管发育。同样，S1P 转运蛋白 spns2 也与 s1pr1 合作。我们提出细胞外 S1P 通过血管 S1P 受体来调节血管发育。
