Heller Regine, Chang Qing, Ehrlich Gunter, Hsieh Sherry N, Schoenwaelder Simone M, Kuhlencordt Peter J, Preissner Klaus T, Hirsch Emilio, Wetzker Reinhard
Center for Molecular Biomedicine, Institute of Molecular Cell Biology, Friedrich Schiller University, Jena, Am Leutragraben 3, 07743 Jena, Germany.
Cardiovasc Res. 2008 Oct 1;80(1):96-105. doi: 10.1093/cvr/cvn159. Epub 2008 Jun 16.
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 PI3Kbeta and gamma isoforms and their downstream effector pathways in mediating endothelial cell migration induced by S1P.
Experiments were performed in human umbilical vein endothelial cells (HUVEC) and murine lung endothelial cells (MLEC). A combination of specific inhibitors, RNA interference, and PI3Kgamma(-/-) mice were used to investigate the role of PI3Kbeta and gamma isoforms in endothelial cell migration. Both PI3Kbeta and gamma isoforms are required for full migration induced by S1P, with Rac1 being a major mediator downstream of both isoforms. In addition, PI3Kbeta but not PI3Kgamma 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 PI3Kbeta or PI3Kgamma.
Our data demonstrate that both PI3Kbeta and PI3Kgamma isoforms are required for S1P-induced endothelial cell migration through activation of Rac1. In addition, PI3Kbeta initiates an Akt-sensitive chemotactic response which is independent of Rac1 and eNOS. Thus, PI3Kbeta and PI3Kgamma have both overlapping and distinct roles in regulating endothelial cell migration, which may underlie S1P-triggered angiogenic differentiation.
鞘氨醇-1-磷酸（S1P）是血管稳态和血管生成的关键调节因子，通过刺激磷酸肌醇3-激酶（PI3K）促进内皮细胞迁移。本研究旨在确定PI3Kβ和γ亚型及其下游效应通路在介导S1P诱导的内皮细胞迁移中的作用。
实验在人脐静脉内皮细胞（HUVEC）和小鼠肺内皮细胞（MLEC）中进行。使用特异性抑制剂、RNA干扰和PI3Kγ基因敲除小鼠的组合来研究PI3Kβ和γ亚型在内皮细胞迁移中的作用。S1P诱导的完全迁移需要PI3Kβ和γ亚型，Rac1是这两种亚型下游的主要介导因子。此外，PI3Kβ而非PI3Kγ通过Akt介导迁移，但独立于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激活对趋化反应有贡献，且独立于PI3Kβ或PI3Kγ。
我们的数据表明，PI3Kβ和PI3Kγ亚型均通过激活Rac1参与S1P诱导的内皮细胞迁移。此外，PI3Kβ启动了一种对Akt敏感的趋化反应，该反应独立于Rac1和eNOS。因此，PI3Kβ和PI3Kγ在调节内皮细胞迁移中具有重叠和不同的作用，这可能是S1P触发血管生成分化的基础。
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