Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration

Mariona Graupera, Julie Guillermet-Guibert, Lazaros C Foukas, Li-Kun Phng, Robert J Cain, Ashreena Salpekar, Wayne Pearce, Stephen Meek, Jaime Millan, Pedro R Cutillas, Andrew J H Smith, Anne J Ridley, Christiana Ruhrberg, Holger Gerhardt, Bart Vanhaesebroeck

Research output: Contribution to journalArticlepeer-review

Abstract

Phosphoinositide 3-kinases (PI3Ks) signal downstream of multiple cell-surface receptor types. Class IA PI3K isoforms couple to tyrosine kinases and consist of a p110 catalytic subunit (p110alpha, p110beta or p110delta), constitutively bound to one of five distinct p85 regulatory subunits. PI3Ks have been implicated in angiogenesis, but little is known about potential selectivity among the PI3K isoforms and their mechanism of action in endothelial cells during angiogenesis in vivo. Here we show that only p110alpha activity is essential for vascular development. Ubiquitous or endothelial cell-specific inactivation of p110alpha led to embryonic lethality at mid-gestation because of severe defects in angiogenic sprouting and vascular remodelling. p110alpha exerts this critical endothelial cell-autonomous function by regulating endothelial cell migration through the small GTPase RhoA. p110alpha activity is particularly high in endothelial cells and preferentially induced by tyrosine kinase ligands (such as vascular endothelial growth factor (VEGF)-A). In contrast, p110beta in endothelial cells signals downstream of G-protein-coupled receptor (GPCR) ligands such as SDF-1alpha, whereas p110delta is expressed at low level and contributes only minimally to PI3K activity in endothelial cells. These results provide the first in vivo evidence for p110-isoform selectivity in endothelial PI3K signalling during angiogenesis.
Original languageEnglish
Pages (from-to)662-6
Number of pages5
JournalNature
Volume453
Issue number7195
DOIs
Publication statusPublished - 2008

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