Whole-mount day-10.5 wild-type embryo that has been immunostained for the endothelial marker endomucin and shows a tree-like hierarchy of large and small cephalic vessels. Image courtesy of Mariona Graupera, Institute of Cancer, Queen Mary, University of London (QMUL), London, UK.

Phosphoinositide 3-kinases (PI3Ks) are involved in cell signalling and the regulation of cell growth. Class IA PI3K isoforms couple to Tyr kinases and consist of a p110 catalytic subunit (p110, p110 or p110) that is 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 or their mechanism of action in endothelial cells during angiogenesis. Bart Vanhaesebroeck and colleagues provide the first in vivo evidence for p110-isoform selectivity in PI3K signalling during angiogenesis.

Ubiquitous knockout of p110 causes angiogenesis defects at mid-gestation. However, it is unclear whether this defect is due to the loss of p110 or due to the resulting upregulation of p85, which has dominant-negative effects on all p110 isoforms. To selectively investigate the role of p110 activity in angiogenesis, the authors devised two genetic approaches: they replaced endogenous p110 with a kinase-dead allele without altering the expression of p110 and p85, and they inactivated p110 in endothelial cells using Cre/loxP-mediated recombination. Ubiquitous or endothelial cell-specific inactivation of p110 led to severe defects in angiogenic sprouting and vascular remodelling and resulted in embryonic lethality. How does p110 exert this crucial endothelial cell-autonomous function?

PI3K activity is required for vascular endothelial growth factor A (VEGFA)-dependent proliferation, migration and survival of endothelial cells. So, does p110 inhibition affect any of these processes? Indeed, p110 activity was found to be preferentially induced by VEGFA and to regulate endothelial cell migration through the activation of the small RhoGTPase RhoA. By contrast, mice with inactive p110 and p110 showed normal vascular development. In endothelial cells, p110 signals downstream of G-protein-coupled receptor ligands, whereas p110 is expressed at low levels and contributes only minimally to PI3K activity. This selectivity makes p110 a tempting drug target for the inhibition of tumour angiogenesis.

Author: Ekat Kritikou - Copyright © 2008 Nature Publishing Group, a division of MacMillan Publishers Limited; used with permission