Leading science, pioneering therapies
CRM Publications

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

TitleAngiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration.
Publication TypeJournal Article
Year of Publication2008
AuthorsGraupera M, Guillermet-Guibert J, Foukas LC, Phng L-K, Cain RJ, Salpekar A, Pearce W, Meek S, Millan J, Cutillas PR, Smith AG, Ridley AJ, Ruhrberg C, Gerhardt H, Vanhaesebroeck B
Date Published2008 May 29
KeywordsAnimals, Cell Movement, Cells, Cultured, Class I Phosphatidylinositol 3-Kinases, Endothelial Cells, Female, Humans, Mice, Neovascularization, Physiologic, Phosphatidylinositol 3-Kinases, Rats, rho GTP-Binding Proteins, RNA Interference, Signal Transduction, Vascular Endothelial Growth Factor A, Wounds and Injuries

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.

Alternate JournalNature
PubMed ID18449193
Grant ListBB/C505659/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
G0601093 / / Medical Research Council / United Kingdom
G0601093(79633) / / Medical Research Council / United Kingdom
G0700711 / / Medical Research Council / United Kingdom
/ / Cancer Research UK / United Kingdom