Sphingosine 1-Phosphate Receptor Signaling Regulates Proper Embryonic Vascular Patterning
Sphingosine 1-Phosphate Receptor Signaling Regulates Proper Embryonic Vascular Patterning
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DOI：
10.1074/jbc.m112.427344
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发表时间：
2013-01-25
影响因子：
4.8
通讯作者：
Hla, Timothy
中科院分区：
文献类型：
--
作者：
Mendelson, Karen;Zygmunt, Tomasz;Hla, Timothy
1-磷酸鞘氨醇（S1 P）与G蛋白偶联受体（S1 P（1-5））结合，调节多种生理效应，尤其是血管和免疫系统中的生理效应。血管系统中的S1 P受体主要在哺乳动物中表征。在这里，我们报告的S1 P受体和代谢酶是保守的斑马鱼Danio rerio的基因组中。生物信息学分析确定了斑马鱼基因组中的7个S1 P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S1 P以及高血浆神经酰胺和鞘氨醇。吗啉代介导的s1 pr 1基因敲低可导致全身和心包水肿、血液循环丧失和血管缺损，其特征为节段间血管的血管化减少、节段间和轴向血管的增殖减少以及尾静脉丛的增生。s1 pr 2基因以前被认为是细胞迁移和心脏发育的调节因子，但其在血管生成中的作用尚不清楚。然而，当S1 PR 1和S1 PR 2的表达被抑制时，观察到严重减少的节间血管的血管发育与剂量的S1 PR 1 morpholino单独不会引起任何明显的血管缺陷，这表明S1 PR 1和S1 PR 2的功能合作，以调节斑马鱼的血管发育。类似地，S1 P转运蛋白spns 2也与s1 pr 1合作。我们认为细胞外S1 P通过血管S1 P受体来调节血管发育。
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.