Regulation of hypoxia-inducible factor 1α and induction of vascular endothelial growth factor in a rat neonatal stroke model

Stroke is a devastating condition occurring in at least 1 in 4000 live births in the neonatal period. Since hypoxia-inducible factor (HIF)-1alpha can modulate ischemic injury via induction of target genes that may protect cells against ischemia, and is induced after preconditioning by hypoxia in the neonatal rat brain hypoxia-ischemia model, we evaluated whether HIF-1alpha is induced after focal ischemia-reperfusion, a model for neonatal stroke. We developed an ischemia-reperfusion model in postnatal day 10 (P10) rats by transiently occluding the middle cerebral artery (MCA) for 1.5 h. The MCA territory was reperfused for 0, 4, 8, or 24 h and the expression of HIF-1alpha and its target gene, vascular endothelial growth factor (VEGF), were delineated. HIF-1alpha protein and VEGF protein peaked at 8 h, and declined subsequently at 24 h in injured cortex following 1.5 h of MCA occlusion. Double-immunolabeling indicated that both HIF-1alpha and VEGF are expressed together in neurons with a similar time course of expression. The presence of HIF-1alpha and VEGF after moderate ischemia-reperfusion injury suggests potential avenues to exploit for neuroprotection. (C) 2003 Elsevier Inc. All rights reserved.