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 PI3Kβ and γ 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 PI3Kγ−/− mice were used to investigate the role of PI3Kβ and γ isoforms in endothelial cell migration. Both PI3Kβ and γ isoforms are required for full migration induced by S1P, with Rac1 being a major mediator downstream of both isoforms. In addition, PI3Kβ but not PI3Kγ 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 PI3Kγ. Our data demonstrate that both PI3Kβ and PI3Kγ 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 PI3Kγ have both overlapping and distinct roles in regulating endothelial cell migration, which may underlie S1P-triggered angiogenic differentiation.