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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >VEGF induces S1P(1) receptors in endothelial cells: Implications for cross-talk between sphingolipid and growth factor receptors
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VEGF induces S1P(1) receptors in endothelial cells: Implications for cross-talk between sphingolipid and growth factor receptors

机译：VEGF诱导内皮细胞中的S1P（1）受体：鞘脂和生长因子受体之间的串扰的影响。

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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. [References: 43]
机译：1-磷酸鞘氨醇（S1P）是一种血小板衍生的鞘脂，与S1P（1）（EDG-1）受体结合并激活NO合酶（eNOS）的内皮亚型。 S1P和多肽生长因子血管内皮生长因子（VEGF）独立发挥作用，调节血管生成并激活eNOS。在这些研究中，我们探讨了S1P和VEGF信号通路之间的相互影响。用VEGF（10 ng / ml）处理培养的牛主动脉内皮细胞时，S1P（1）蛋白和mRNA的表达增加了约4倍。在加入VEGF的30分钟内即可看到VEGF的S1P（1）上调，并在1.5 h后达到最大值。相反，通过VEGF处理，缓激肽B2受体和支架蛋白caveolin-1的表达均未改变。在其生理浓度范围内，VEGF促进S1P（1）表达的EC50约为2 ng / ml。酪氨酸激酶抑制剂染料木黄酮和PKC抑制剂钙磷蛋白C减弱了VEGF对S1P（1）的诱导。牛主动脉内皮细胞与VEGF（10 ng / ml孵育90分钟）的预孵育显着增强了随后的S1P依赖性eNOS激活。 VEGF对培养的内皮细胞的预处理还显着增强了Ser-1179上S1P促进的eNOS磷酸化，以及S1P介导的激酶Akt激活。在离体大鼠动脉中，VEGF预处理显着增强了S1P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S1P（1）受体的表达，与SIP增强的细胞内信号传导反应以及S1P介导的血管舒张作用增强有关。我们建议，VEGF的作用是通过促进S1P（1）受体的诱导来使血管内皮对脂质介体的作用敏感，这代表了脉管系统中受体调节的eNOS信号传导途径之间潜在的重要交流点。 [参考：43]

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