HIF1α Signaling in the Endogenous Protective Responses after Neonatal Brain Hypoxia-Ischemia

Hypoxia-inducible factor 1 alpha (HIF1 alpha) is a key regulator of oxygen homeostasis, and its target genes mediate adaptive, protective, and pathological processes. The role of HIF1 alpha in neuronal survival is controversial and the brain maturation stage is important in determining its function in brain ischemia or hypoxia-ischemia (HI). In this study, we used neuron-specific HIF1 alpha knockout mice at postnatal day 9 (P9), and immature cortical neurons (days 7-8 in vitro) treated with the HIF1 alpha inhibitor 2-methoxyestradiol (2ME2) or stabilizer dimethyloxalylglycine (DMOG), to examine the function of neuronal HIF1 alpha in neonatal HI in vivo (Vannucci model) and in vitro (oxygen glucose deprivation, OGD). Inhibition of HIF1 alpha with 2ME2 in primary neurons or deletion of neuronal HIF1 alpha in P9 mice increased both necrotic and apoptotic cell death following HI, as evaluated by the protein levels of 145/150-kDa and 120-kDa spectrin breakdown products 24 h after HI. DMOG attenuated neuronal death right after OGD. Acute pharmacological manipulation of HIF1 alpha synchronously regulated the expression of its targets, vascular endothelial growth factor (VEGF) and erythropoietin (Epo), in the same manner. The in vivo findings agree with our previous data using the same HIF1 alpha-deficient mice at an earlier age. This study confirms the role of neuronal HIF1 alpha signaling in the endogenous protective responses following HI in the developing brain.