Vascular endothelial growth factor is an angiogenic peptide that binds to tyrosine kinase receptors on target cells to activate signal transduction pathways involving phosphatidylinositol 3′-kinase and the serine–threonine protein kinase, Akt. To determine whether this signaling pathway is activated in cerebral ischemia, we examined the expression of vascular endothelial growth factor receptors 1 and 2, and phosphatidylinositol 3′-kinase-activated phospho-Akt, in the cerebral cortex and hippocampus following transient global cerebral ischemia in the rat. Western blot analysis and immunocytochemistry demonstrated induction of vascular endothelial growth factor receptor 1 and 2 expression, and of anti-phosphatidylinositol 3′-kinase-immunoprecipitated phospho-Akt, in vulnerable regions of the cortex and hippocampus after 15min of global ischemia and 4–72h of reperfusion. These findings demonstrate that vascular endothelial growth factor receptors and receptor-coupled signal transduction pathways are induced in ischemic brain in vivo, and could therefore participate in endogenous neuroprotective responses to ischemia.