Neuronal HIF‐1α in the nucleus tractus solitarius contributes to ventilatory acclimatization to hypoxia

KEY POINTS: We hypothesized that hypoxia inducible factor 1alpha (HIF-1alpha) in central nervous system (CNS) respiratory centers is necessary for ventilatory acclimatization to hypoxia (VAH); VAH is a time-dependent increase in baseline ventilation and the hypoxic ventilatory response (HVR) occurring over days to weeks of chronic sustained hypoxia (CH). Constitutive deletion of HIF-1alpha in CNS neurons in transgenic mice tended to blunt the increase in HVR that occurs in wild-type mice with CH. Conditional deletion of HIF-1alpha in glutamatergic neurons of the NTS during CH significantly decreased ventilation in acute hypoxia but not normoxia in CH mice. These effects are not explained by changes in metabolic rate nor CO2 and there were no changes in the HVR in normoxic mice. HIF-1alpha mediated changes in gene expression in CNS respiratory centers are necessary in addition to plasticity of arterial chemoreceptors for normal VAH. ABSTRACT: Chronic hypoxia (CH) produces a time-dependent increase of resting ventilation and the hypoxic ventilatory response (HVR) that is called ventilatory acclimatization to hypoxia (VAH). VAH involves plasticity in arterial chemoreceptors and the central nervous system (e.g. nucleus tractus solitarius, NTS) but signals for this plasticity are not known. We hypothesized hypoxia inducible factor 1-alpha (HIF-1alpha), an O2 -sensitive transcription factor, is necessary in the NTS for normal VAH. We tested this in two mouse models using loxP-Cre gene deletion. First, HIF-1alpha was constitutively deleted in CNS neurons (CNS-HIF-1alpha(-/-) ) by breeding HIF-1alpha floxed mice with mice expressing Cre-recombinase driven by CaM Kinase II promoter. Second, HIF-1alpha was deleted in NTS neurons in adult mice (NTS-HIF-1alpha(-/-) ) by microinjecting adeno-associated virus that expressed Cre-recombinase in HIF-1alpha floxed mice. In normoxic control mice, HIF-1alpha deletion in the CNS or NTS did not affect ventilation nor the acute HVR (10-15 min hypoxic exposure). In mice acclimatized to CH for one week, ventilation in hypoxia was blunted in CNS-HIF-1alpha(-/-) and significantly decreased in NTS-HIF-1alpha(-/-) compared to control mice (p < 0.0001). These changes were not explained by differences in metabolic rate or CO2 . Immunofluorescence showed that HIF-1alpha deletion in NTS-HIF-1alpha(-/-) was restricted to glutamatergic neurons. The results support that HIF-1alpha is a necessary signal for VAH and the previously described plasticity in glutamatergic neurotransmission in the NTS with CH. HIF-1alpha deletion had no effect on the increase in normoxic ventilation with acclimatization to CH indicating this is a distinct mechanism from the increased HVR with VAH. This article is protected by copyright. All rights reserved.