Overlapping and distinct roles for PI3Kβ and γ isoforms in S1P-induced migration of human and mouse endothelial cells
Overlapping and distinct roles for PI3Kβ and γ isoforms in S1P-induced migration of human and mouse endothelial cells
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DOI：
10.1093/cvr/cvn159
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发表时间：
2008-10-01
影响因子：
10.8
通讯作者：
Wetzker, Reinhard
中科院分区：
文献类型：
--
作者：
Heller, Regine;Chang, Qing;Wetzker, Reinhard
目的神经鞘氨醇-1-磷酸(S1P)是血管内稳态和血管生成的关键调节因子，通过刺激磷脂酰肌醇3-激酶(PI3K)促进内皮细胞迁移。本研究旨在探讨PI3Kβ和γ亚型及其下游效应通路在SLP诱导内皮细胞迁移中的作用。方法与结果在人脐静脉内皮细胞和小鼠肺内皮细胞上进行实验。使用特定的抑制剂、RNA干扰和PI3Kγ(-/-)小鼠的组合来研究PI3Kβ和伽马亚型在内皮细胞迁移中的作用。PI3Kβ和伽马亚型都是S1P诱导的完全迁移所必需的，而rac1是这两种异构体下游的主要介体。此外，PI3Kβ而不是PI3Kγ通过Akt介导迁移，但不依赖于rac1和内皮型一氧化氮合酶(ENOS)。此外，S1P介导的细胞外信号调节激酶(ERK)1/2的激活有助于不依赖于PI3Kβ或PI3Kγ的趋化反应。结论PI3Kβ和PI3Kγ亚型均是S1P通过激活rac1诱导内皮细胞迁移所必需的。此外，PI3Kβ启动Akt敏感的趋化反应，该反应不依赖于rac1和eNOS。因此，PI3Kβ和PI3Kγ在调节内皮细胞迁移方面既有重叠又有不同的作用，这可能是S1P触发血管生成分化的基础。
Aims Sphingosine-1-phosphate (S1P), a key regulator of vascular homeostasis and angiogenesis, promotes endothelial cell migration via stimulation of phosphoinositide 3-kinase (PI3K). The aim of this study was to identify the role of PI3K beta and gamma isoforms and their downstream effector pathways in mediating endothelial cell migration induced by S1P.Methods and results Experiments were performed in human umbilical vein endothelial cells (HUVEC) and murine lung endothelial cells (MLEC). A combination of specific inhibitors, RNA interference, and PI3K gamma(-/-) mice were used to investigate the role of PI3K beta and gamma isoforms in endothelial cell migration. Both PI3K beta and gamma isoforms are required for full migration induced by S1P, with Rac1 being a major mediator downstream of both isoforms. In addition, PI3K beta but not PI3K gamma mediates migration via Akt but independent of Rac1 and endothelial NO synthase (eNOS). Further, a S1P-mediated activation of extracellular signal-regulated kinases (Erk) 1/2 contributes to the chemotactic response independent of PI3K beta or PI3K gamma.Conclusions Our data demonstrate that both PI3K beta and PI3K gamma isoforms are required for S1P-induced endothelial cell migration through activation of Rac1. In addition, PI3K beta initiates an Akt-sensitive chemotactic response which is independent of Rac1 and eNOS. Thus, PI3K beta and PI3K gamma have both overlapping and distinct roles in regulating endothelial cell migration, which may underlie S1P-triggered angiogenic differentiation.