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 PI3Kbeta 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 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. CONCLUSIONS: 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.
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 PI3Kbeta 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 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. CONCLUSIONS: 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.
Authors: Montse Erra; Joan Taltavull; Angelique Gréco; Francisco Javier Bernal; Juan Francisco Caturla; Jordi Gràcia; María Domínguez; Mar Sabaté; Stéphane Paris; Salomé Soria; Begoña Hernández; Clara Armengol; Judit Cabedo; Mónica Bravo; Elena Calama; Montserrat Miralpeix; Martin D Lehner Journal: ACS Med Chem Lett Date: 2016-11-30 Impact factor: 4.345
Authors: Borja L Holgado; Laura Martínez-Muñoz; Juan Antonio Sánchez-Alcañiz; Pilar Lucas; Vicente Pérez-García; Gema Pérez; José Miguel Rodríguez-Frade; Marta Nieto; Oscar Marín; Yolanda R Carrasco; Ana C Carrera; Manuel Alvarez-Dolado; Mario Mellado Journal: Mol Neurobiol Date: 2013-04-19 Impact factor: 5.590
Authors: Tae-Hyun Yoo; Christopher E Pedigo; Johanna Guzman; Mayrin Correa-Medina; Changli Wei; Rodrigo Villarreal; Alla Mitrofanova; Farah Leclercq; Christian Faul; Jing Li; Matthias Kretzler; Robert G Nelson; Markku Lehto; Carol Forsblom; Per-Henrik Groop; Jochen Reiser; George William Burke; Alessia Fornoni; Sandra Merscher Journal: J Am Soc Nephrol Date: 2014-06-12 Impact factor: 10.121
Authors: A Fougerat; N F Smirnova; S Gayral; N Malet; E Hirsch; M P Wymann; B Perret; L O Martinez; M Douillon; M Laffargue Journal: Br J Pharmacol Date: 2012-07 Impact factor: 8.739
Authors: Xueyi Chen; Pavel Zhabyeyev; Abul K Azad; Wang Wang; Rachel A Minerath; Jessica DesAulniers; Chad E Grueter; Allan G Murray; Zamaneh Kassiri; Bart Vanhaesebroeck; Gavin Y Oudit Journal: Cardiovasc Res Date: 2019-07-01 Impact factor: 10.787