Neuronal deficiency of hypoxia-inducible factor 2α increases hypoxic-ischemic brain injury in neonatal mice

The cellular responses to hypoxia or hypoxia-ischemia (HI) are governed largely by the hypoxia-inducible factor (HIF) family of transcription factors. Our previous studies show that HIF-1 alpha induction is an important factor that mediates protective effects in the brain after neonatal HI. In the present study, we investigated the contribution of another closely related HIF alpha isoform, HIF-2 alpha, specifically the neuronal HIF-2 alpha, to brain HI injury. Homozygous transgenic mice with a floxed exon 2 of HIF-2 alpha were bred with CaMKII alpha-Cre mice to generate a mouse line with selective deletion of HIF-2 alpha in forebrain neurons. These mice, along with their wildtype littermates, were subjected to HI at postnatal day 9. Brain injury at different ages was evaluated by the levels of cleaved caspase-3 and spectrin breakdown products at 24 hr; and histologically at 6 days or 3 months after HI. Multiple behavioral tests were performed at 3 months, prior to sacrifice. Loss of neuronal HIF-2 alpha exacerbated brain injury during the acute (24 hr) and subacute phases (6 days), with a trend toward more severe volume loss in the adult brain. The long-term brain function for coordinated movement and recognition memory, however, were not impacted in the neuronal HIF-2 alpha deficient mice. Our data suggest that, similar to HIF-1 alpha, neuronal HIF-2 alpha promotes cell survival in the immature mouse brain. The two HIF alpha isoforms may act through partially overlapping or distinct transcriptional targets to mediate their intrinsic protective responses against neonatal HI brain injury.