Akt down-regulation of p38 signaling provides a novel mechanism of vascular endothelial growth factor-mediated cytoprotection in endothelial cells

Vascular endothelial growth factor (VEGF) utilizes a phosphoinositide 3-kin ase (PI 3-kinase)/Akt signaling pathway to protect endothelial cells from a poptotic death. Here we show that PI 3-kinase/Akt; signaling promotes endot helial cell survival by inhibiting p38 mitogen-activated protein kinase (MA PK)-dependent apoptosis. Blockade of the PI 3-kinase or Akt pathways in con junction with serum withdrawal stimulates p38-dependent apoptosis. Blockade of PI 3-kinase/Akt also led to enhanced VEGF activation of p38 and apoptos is. In this context, the pro-apoptotic effect of VEGF is attenuated by the p38 MAPK inhibitor SE203580. VEGF stimulation of endothelial cells or infec tion with an adenovirus expressing constitutively active Akt; causes MEKK3 phosphorylation, which is associated with decreased MEKK3 kinase activity a nd down-regulation of MKK3/6 and p38 MAPK activation. Conversely, activatio n-deficient Akt decreases VEGF-stimulated MEKK3 phosphorylation and increas es MKK/p38 activation. Activation of MKK3/6 is not dependent on Rac activat ion since dominant negative Rac does not decrease p38 activation triggered by inhibition of PI 3-kinase. Thus, cross-talk between the Akt and p38 MAPK pathways may regulate the level of cytoprotection versus apoptosis and is a new mechanism to explain the cytoprotective actions of Akt.