Overlapping and distinct roles for PI3Kβ and γ isoforms in S1P-induced migration of human and mouse endothelial cells

被引：43

作者：

Heller, Regine ^{[1
]}

Chang, Qing ^{[1
]}

Ehrlich, Gunter ^{[1
]}

Hsieh, Sherry N. ^{[1
]}

Schoenwaelder, Simone M. ^{[2
]}

Kuhlencordt, Peter J. ^{[3
]}

Preissner, Klaus T. ^{[4
]}

Hirsch, Emilio ^{[5
]}

Wetzker, Reinhard ^{[1
]}

机构：

[1] Univ Jena, Inst Mol Cell Biol, Ctr Mol Biomed, D-07743 Jena, Germany

[2] Monash Univ, Australian Ctr Blood Dis, Alfred Med Res Ctr & Educ Precinct AMREP, Melbourne, Vic 3004, Australia

[3] Univ Wurzburg, Univ Klinikum, Herz Kreislaufzentrum, Med Klin 1, Wurzburg, Germany

[4] Univ Giessen, Fac Med, Inst Biochem, Giessen, Germany

[5] Univ Turin, Ctr Mol Biotechnol, Dept Genet Biol & Biochem, Turin, Italy

来源：

CARDIOVASCULAR RESEARCH | 2008年 / 80卷 / 01期

关键词：

angiogenesis; endothelial function; lipid signalling; protein kinases; signal transduction;

D O I：

10.1093/cvr/cvn159

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：96 / 105

页数：10

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