Inoki Isao, Takuwa Noriko, Sugimoto Naotoshi, Yoshioka Kazuaki, Takata Shigeo, Kaneko Shuichi, Takuwa Yoh
Department of Physiology, Graduate School of Medical Sciences, Kanazawa University, Ishikawa 920-8640, Japan.
Biochem Biophys Res Commun. 2006 Jul 21;346(1):293-300. doi: 10.1016/j.bbrc.2006.05.119. Epub 2006 Jun 2.
We speculated that the sphingosine-1-phosphate (S1P) receptor S1P(2), which uniquely inhibits cell migration, might mediate inhibitory effects on endothelial cell migration and angiogenesis, different from S1P(1) and S1P(3). Mouse vascular endothelial cells, which endogenously express S1P(2) and S1P(3), but not S1P(1), responded to S1P and epidermal growth factor (EGF) with stimulation of Rac, migration, and the formation of tube-like structures on the Matrigel. The S1P(3)-antagonist VPC-23019 abolished S1P-induced, G(i)-dependent Rac stimulation, cell migration, and tube formation, whereas the S1P(2)-antagonist JTE-013 enhanced these S1P-induced responses, suggesting that S1P(2) exerts inhibitory effects on endothelial Rac, migration, and angiogenesis. S1P(2) overexpression markedly augmented S1P-induced, G(i)-independent inhibition of EGF-induced migration and tube formation. Finally, the blockade of S1P(2) by JTE-013 potentiated S1P-induced stimulation of angiogenesis in vivo in the Matrigel implant assay. These observations indicate that in contrast to S1P(1) and S1P(3), S1P(2) negatively regulates endothelial morphogenesis and angiogenesis most likely through down-regulating Rac.
我们推测，独特地抑制细胞迁移的1-磷酸鞘氨醇（S1P）受体S1P(2)，可能介导对内皮细胞迁移和血管生成的抑制作用，这与S1P(1)和S1P(3)不同。内源性表达S1P(2)和S1P(3)但不表达S1P(1)的小鼠血管内皮细胞，对S1P和表皮生长因子（EGF）产生反应，表现为Rac激活、细胞迁移以及在基质胶上形成管状结构。S1P(3)拮抗剂VPC-23019消除了S1P诱导的、G(i)依赖性的Rac激活、细胞迁移和管状结构形成，而S1P(2)拮抗剂JTE-013增强了这些S1P诱导的反应，这表明S1P(2)对内皮细胞的Rac、迁移和血管生成具有抑制作用。S1P(2)的过表达显著增强了S1P诱导的、G(i)非依赖性的对EGF诱导的迁移和管状结构形成的抑制。最后，在基质胶植入试验中，JTE-013对S1P(2)的阻断增强了S1P诱导的体内血管生成刺激。这些观察结果表明，与S1P(1)和S(3)不同，S1P(2)最有可能通过下调Rac对内皮细胞形态发生和血管生成起负向调节作用。
