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Cardiovascular Research Advance Access first published online on June 16, 2008
This version [Corrected Proof] published online on July 2, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn159
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

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

Regine Heller1,*, Qing Chang1, Gunter Ehrlich1, Sherry N. Hsieh1, Simone M. Schoenwaelder2, Peter J. Kuhlencordt3, Klaus T. Preissner4, Emilio Hirsch5 and Reinhard Wetzker1

1 Center for Molecular Biomedicine, Institute of Molecular Cell Biology, Friedrich Schiller University, Jena, Am Leutragraben 3, 07743 Jena, Germany
2 Australian Centre for Blood Diseases, Monash University, Alfred Medical Research Centre and Education Precinct (AMREP), Melbourne, Victoria, Australia
3 Medizinische Klinik I/Herz-Kreislaufzentrum, Universitätsklinikum, Julius Maximilian University, Würzburg, Germany
4 Institute for Biochemistry, Medical Faculty, Justus Liebig University, Giessen, Germany
5 Department of Genetics, Biology and Biochemistry, Center for Molecular Biotechnology, University of Torino, Torino, Italy

* Corresponding author. Tel: +49 3641 938 750; fax: +49 3641 938 752. E-mail address: regine.heller{at}mti.uni-jena.de

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 PI3Kβ 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 PI3Kβ and {gamma} isoforms in endothelial cell migration. Both PI3Kβ and {gamma} isoforms are required for full migration induced by S1P, with Rac1 being a major mediator downstream of both isoforms. In addition, PI3Kβ 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 PI3Kβ or PI3K{gamma}.

Conclusions: Our data demonstrate that both PI3Kβ and PI3K{gamma} isoforms are required for S1P-induced endothelial cell migration through activation of Rac1. In addition, PI3Kβ initiates an Akt-sensitive chemotactic response which is independent of Rac1 and eNOS. Thus, PI3Kβ and PI3K{gamma} have both overlapping and distinct roles in regulating endothelial cell migration, which may underlie S1P-triggered angiogenic differentiation.

KEYWORDS Angiogenesis; Endothelial function; Lipid signalling; Protein kinases; Signal transduction

Time for primary review: 22 days


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