Lee O H, Kim Y M, Lee Y M, Moon E J, Lee D J, Kim J H, Kim K W, Kwon Y G
Institute of Environmental and Life Science, the Hallym Academy of Science, Hallym University, Chunchon, Kangwon-Do, 200-702, Korea.
Biochem Biophys Res Commun. 1999 Nov 2;264(3):743-50. doi: 10.1006/bbrc.1999.1586.
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite abundantly stored in platelets and released upon platelet activation. Recently, S1P has been postulated for its potential roles in angiogenesis. In this study, we provided several lines of evidence showing that S1P has angiogenic activity. In vitro, S1P stimulated DNA synthesis and chemotactic motility of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner, reaching a near maximum at 1 microM. S1P also significantly induced tube formation of HUVECs on Matrigel. Matrigel plug assay in mice revealed that S1P promotes angiogenesis in vivo. In addition, exposure of HUVECs to S1P led to rapid activation of extracellular signal-regulated kinases (ERKs) and p38 mitogen-activated protein kinase (p38 MAPK) in a pertussis toxin (PTX)-sensitive manner. Notably, HUVEC migration and tube formation in response to S1P were completely blocked by pretreatment with PTX. Further, the MEK inhibitor U0126 markedly inhibited S1P-induced tube formation but S1P-induced migration was not affected by inhibition of ERK and p38 MAPK. Taken together, these results indicate that S1P induces angiogenesis predominantly via G(i) protein-coupled receptors in endothelial cells and suggest that S1P may act as an important modulator of platelet-induced angiogenesis.
1-磷酸鞘氨醇（S1P）是一种生物活性鞘脂代谢产物，大量储存在血小板中，并在血小板激活时释放。最近，S1P因其在血管生成中的潜在作用而被提出。在本研究中，我们提供了几条证据表明S1P具有血管生成活性。在体外，S1P以剂量依赖的方式刺激人脐静脉内皮细胞（HUVECs）的DNA合成和趋化运动，在1 microM时达到接近最大值。S1P还显著诱导HUVECs在基质胶上形成管腔。小鼠基质胶栓试验表明S1P在体内促进血管生成。此外，将HUVECs暴露于S1P会导致细胞外信号调节激酶（ERKs）和p38丝裂原活化蛋白激酶（p38 MAPK）以百日咳毒素（PTX）敏感的方式快速激活。值得注意的是，用PTX预处理可完全阻断HUVECs对S1P的迁移和管腔形成反应。此外，MEK抑制剂U0126显著抑制S1P诱导的管腔形成，但S1P诱导的迁移不受ERK和p38 MAPK抑制的影响。综上所述，这些结果表明S1P主要通过内皮细胞中的G(i)蛋白偶联受体诱导血管生成，并提示S1P可能作为血小板诱导血管生成的重要调节因子。
