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Angiogenesis selectively requires the p110α isoform of PI3K to control endothelial cell migration


Phosphoinositide 3-kinases (PI3Ks) signal downstream of multiple cell-surface receptor types. Class IA PI3K isoforms1 couple to tyrosine kinases and consist of a p110 catalytic subunit (p110α, p110β or p110δ), constitutively bound to one of five distinct p85 regulatory subunits. PI3Ks have been implicated in angiogenesis2,3,4,5, 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 p110α activity is essential for vascular development. Ubiquitous or endothelial cell-specific inactivation of p110α led to embryonic lethality at mid-gestation because of severe defects in angiogenic sprouting and vascular remodelling. p110α exerts this critical endothelial cell-autonomous function by regulating endothelial cell migration through the small GTPase RhoA. p110α activity is particularly high in endothelial cells and preferentially induced by tyrosine kinase ligands (such as vascular endothelial growth factor (VEGF)-A). In contrast, p110β in endothelial cells signals downstream of G-protein-coupled receptor (GPCR) ligands such as SDF-1α, whereas p110δ 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.

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Figure 1: Inactivation of p110α in the germline (p110α D933A/D933A ) or in endothelial cells ( Tie2 Cre/p110α flox/flox ) leads to severe defects in angiogenic sprouting and vascular remodelling.
Figure 2: p110α is the main provider of PI3K signalling in endothelial cells under basal and VEGF-A-stimulated conditions.
Figure 3: p110α controls endothelial cell migration in vitro and in vivo.
Figure 4: p110α is a positive regulator of RhoA in endothelial cells.


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We thank F. Ramadani and K. Okkenhaug (Babraham Institute, Cambridge), E. Cernuda (Hospital Universitario Central de Asturias), T. Makinen (Cancer Research UK London Research Institute), K. Hodivala-Dilke, A. Reynolds and G. D’Amico (Institute of Cancer, Queen Mary, University of London), P. Villalonga (Universitat de les Illes Balears, Spain) and members of the Vanhaesebroeck laboratory (especially N. Osborne, C. See and M. Whitehead) for help and advice, E. Wagner (Research Institute of Molecular Pathology, Vienna), E. Dejana (Institute of Molecular Oncology, Milan), G. Balconi (Mario Negri Institute for Pharmacological Research, Milan), M. Yanagisawa (University of Texas Southwestern Medical Center, Dallas), D. Vestweber (Max-Planck Institute, Muenster), C. Rommel, M. Camps and T. Ruckle (Merck-Serono, Geneva) and Piramed (Slough, UK) for mice and reagents. Personal support was from EMBO (M.G., J.G.-G.), Cancer Research UK (M.G.) and the Fondation pour la Recherche Médicale and the European Union Marie Curie (J.G.-G.). Work in the Vanhaesebroeck laboratory was supported by the Ludwig Institute for Cancer Research Institute, the Biotechnology and Biological Sciences Research Council (BB/C505659/1), the Association for International Cancer Research, European Union (FP6-502935), Cancer Research UK and Barts and the London Charity. R.J.C. is supported by an Association for International Cancer Research grant to A.J.R. (07-0173). L.-K.P. and H.G. are supported by Cancer Research UK.

Author Contributions All authors designed research and analysed data. M.G., J.G.-G., L.C.F., L.-K.P., R.J.C., A.S., W.P., S.M. and P.R.C. performed research. M.G., H.G. and B.V. wrote the paper.

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Correspondence to Holger Gerhardt or Bart Vanhaesebroeck.

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B.V. is a consultant for PIramed Pharma.

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Graupera, M., Guillermet-Guibert, J., Foukas, L. et al. Angiogenesis selectively requires the p110α isoform of PI3K to control endothelial cell migration. Nature 453, 662–666 (2008).

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