Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability
Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability
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DOI：
10.1074/jbc.m306896200
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发表时间：
2003-11-21
影响因子：
4.8
通讯作者：
Hla, T
中科院分区：
文献类型：
--
作者：
Sanchez, T;Estrada-Hernandez, T;Hla, T
FTY720是一种有效的免疫抑制剂，在体内被磷酸化为FTY720-P，它是一种高亲和力的1-磷酸鞘氨醇(S1P)受体激动剂。FTY720对血管细胞的影响尚未得到解决，血管细胞是S1P作用的主要目标。我们现在报道FTY720被鞘氨醇激酶-2代谢激活，并在体外和体内被磷酸化的FTY720(FTY720-P)有效地激活血管内皮细胞功能。FTY720与血管内皮细胞孵育后，神经鞘氨醇激酶活性发生磷酸化，形成FTY720-P。鞘氨醇激酶-2在人胚胎肾293T异源表达系统中有效地磷酸化FTY720。FTY720-P作用于内皮细胞，可刺激细胞外信号活化蛋白激酶和Akt的磷酸化，并黏附连接组装，促进细胞存活。FTY720-P的作用被百日咳毒素抑制，提示需要G(I)偶联的S1P受体。事实上，FTY720-P可有效逆转血管内皮细胞生长因子诱导的跨单层通透性。此外，在小鼠体内口服FTY720可以有效地阻断血管内皮生长因子诱导的血管通透性。这些发现表明，FTY720或其类似物可能在血管通透性的治疗调节中有用，血管通透性是血管生成、炎症和脓毒症、缺氧和实体瘤生长等病理条件中的一个重要过程。
FTY720, a potent immunosuppressive agent, is phosphorylated in vivo into FTY720-P, a high affinity agonist for sphingosine 1-phosphate (S1P) receptors. The effects of FTY720 on vascular cells, a major target of S1P action, have not been addressed. We now report the metabolic activation of FTY720 by sphingosine kinase-2 and potent activation of vascular endothelial cell functions in vitro and in vivo by phosphorylated FTY720 (FTY720-P). Incubation of endothelial cells with FTY720 resulted in phosphorylation by sphingosine kinase activity and formation of FTY720-P. Sphingosine kinase-2 effectively phosphorylated FTY720 in the human embryonic kidney 293T heterologous expression system. FTY720-P treatment of endothelial cells stimulated extracellular signal-activated kinase and Akt phosphorylation and adherens junction assembly and promoted cell survival. The effects of FTY720-P were inhibited by pertussis toxin, suggesting the requirement for G(i)-coupled S1P receptors. Indeed, transmonolayer permeability induced by vascular endothelial cell growth factor was potently reversed by FTY720-P. Furthermore, oral FTY720 administration in mice potently blocked VEGF-induced vascular permeability in vivo. These findings suggest that FTY720 or its analogs may find utility in the therapeutic regulation of vascular permeability, an important process in angiogenesis, inflammation, and pathological conditions such as sepsis, hypoxia, and solid tumor growth.