Abstract
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.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
