Overlapping and distinct roles for PI3Kβ and γ isoforms in S1P-induced migration of human and mouse endothelial cells
Copyright policy )Overlapping and distinct roles for PI3Kβ and γ isoforms in S1P-induced migration of human and mouse endothelial cells
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.
- University of Turin Italy
- Justus Liebig University Giessen Germany
- Monash University Australia
- Friedrich Schiller University Jena Germany
Mice, Knockout, rac1 GTP-Binding Protein, Angiogenesis; Endothelial function; Lipid signalling; Protein kinases; Signal transduction, Nitric Oxide Synthase Type III, Endothelial Cells, Isoenzymes, Mice, Phosphatidylinositol 3-Kinases, Cell Movement, Sphingosine, Animals, Class Ib Phosphatidylinositol 3-Kinase, Humans, Lysophospholipids, Phosphorylation, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins c-akt, Cells, Cultured
Mice, Knockout, rac1 GTP-Binding Protein, Angiogenesis; Endothelial function; Lipid signalling; Protein kinases; Signal transduction, Nitric Oxide Synthase Type III, Endothelial Cells, Isoenzymes, Mice, Phosphatidylinositol 3-Kinases, Cell Movement, Sphingosine, Animals, Class Ib Phosphatidylinositol 3-Kinase, Humans, Lysophospholipids, Phosphorylation, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins c-akt, Cells, Cultured
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