VEGF induces S1P1 receptors in endothelial cells:: Implications for cross-talk between sphingolipid and growth factor receptors
VEGF induces S1P1 receptors in endothelial cells:: Implications for cross-talk between sphingolipid and growth factor receptors
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DOI：
10.1073/pnas.1934494100
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发表时间：
2003-09-16
影响因子：
11.1
通讯作者：
Michel, T
中科院分区：
文献类型：
--
作者：
Igarashi, J;Erwin, PA;Michel, T
1-磷酸鞘氨醇（S1 P）是一种血小板源性鞘脂，可与S1 P（1）（EDG-1）受体结合并激活内皮型NO合酶（eNOS）。S1 P和多肽生长因子血管内皮生长因子（VEGF）独立调节血管生成并激活eNOS。在这些研究中，我们探讨了S1 P和VEGF信号通路之间的相互作用。当用VEGF（10 ng/ml）处理培养的牛主动脉内皮细胞时，S1 P（1）蛋白和mRNA的表达增加了约4倍。VEGF对S1 P（1）的上调作用在加入VEGF后30 min内出现，并在1.5 h后达到最大。相比之下，血管内皮生长因子治疗既不改变缓激肽B2受体的表达，也不改变支架蛋白小窝蛋白-1。VEGF诱导S1 P（1）表达的EC_（50）约为2ng/ml，在其生理浓度范围内。酪氨酸激酶抑制剂genistein和PKC抑制剂calphostin C可减弱VEGF诱导的S1 P（1）。牛主动脉内皮细胞与VEGF（10 ng/ml，90分钟）预孵育显着增强随后的S1 P依赖性eNOS激活。VEGF预处理培养的内皮细胞也显着增强S1 P促进eNOS磷酸化的Ser-1179，以及S1 P介导的激酶Akt的激活。在离体大鼠动脉中，VEGF预处理显著增强S1 P介导的血管舒张和eNOS Ser-1179磷酸化。综上所述，这些数据表明VEGF特异性诱导S1 P（1）受体的表达，与SIP增强的细胞内信号应答和S1 P介导的血管舒张增强相关。我们认为VEGF通过促进S1 P（1）受体的诱导，使血管内皮对脂质介质的作用敏感，这代表了血管系统中受体调节的eNOS信号通路之间的潜在重要交叉点。
Sphingosine 1-phosphate (S1P) is a platelet-derived sphingolipid that binds to S1P(1) (EDG-1) receptors and activates the endothelial isoform of NO synthase (eNOS). S1P and the polypeptide growth factor vascular endothelial growth factor (VEGF) act independently to modulate angiogenesis and activate eNOS. In these studies, we explored the cross-talk between S1P and VEGF signaling pathways. When cultured bovine aortic endothelial cells were treated with VEGF (10 ng/ml), the expression of S1P(1) protein and mRNA increased by approximate to4-fold. S1P(1) up-regulation by VEGF was seen within 30 min of VEGF addition and reached a maximum after 1.5 h. By contrast, expression of neither bradykinin B2 receptors nor the scaffolding protein caveolin-1 was altered by VEGF treatment. The EC50 for VEGF-promoted induction of S1P(1) expression was approximate to2 ng/ml, within its physiological concentration range. S1P(1) induction by VEGF was attenuated by the tyrosine kinase inhibitor genistein and by the PKC inhibitor calphostin C. Preincubation of bovine aortic endothelial cells with VEGF (10 ng/ml for 90 min) markedly enhanced subsequent S1P-dependent eNOS activation. VEGF pretreatment of cultured endothelial cells also markedly potentiated S1P-promoted eNOS phosphorylation at Ser-1179, as well as S1P-mediated activation of kinase Akt. In isolated rat arteries, VEGF pretreatment markedly potentiated S1P-mediated vasorelaxation and eNOS Ser-1179 phosphorylation. Taken together, these data indicate that VEGF specifically induces expression of S1P(1) receptors, associated with enhanced intracellular signaling responses to SIP and the potentiation of S1P-mediated vasorelaxation. We suggest that VEGF acts to sensitize the vascular endothelium to the effects of lipid mediators by promoting the induction of S1P(1) receptors, representing a potentially important point of cross-talk between receptor-regulated eNOS signaling pathways in the vasculature.