Selective cardiorespiratory and catecholaminergic areas express the hypoxia‐inducible factor‐1α (HIF‐1α) under in vivo hypoxia in rat brainstem

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Abstract
Under severe oxygen deprivation, all cells are able to express the transcription factor HIF‐1, which activates a wide range of genes. Under tolerable hypoxia, chemosensory inputs are integrated in brainstem areas, which control cardiorespiratory responses. However, the molecular mechanisms of this functional acclimatization are unknown. We investigated when and where the inducible HIF‐1α subunit is expressed in the rat brainstem in vivo, under physiological hypoxia. The regional localization of HIF‐1α mRNA and protein was determined by in situ hybridization and immunocytochemistry in adult male rats exposed to moderate hypoxia (10% O2) for 1–6 h. HIF‐1α protein was found in cell types identified by immunocytochemistry as catecholaminergic neurons. Hypoxia induced HIF‐1α mRNA and protein in only some parts of the brainstem located dorsomedially and ventrolaterally, which are those involved in the cardiorespiratory control. No labelling was detected under normoxia. The protein was detected in glia and neurons after 1 and 6 h of hypoxia, respectively. A subset of A2C2 and A1C1 catecholaminergic neurons colocalized tyrosine hydroxylase and HIF‐1α proteins under hypoxia, but no HIF‐1α was detected in more rostral catecholaminergic areas. In contrast to cardiorespiratory areas, HIF‐1α protein was already present under normoxia in glial cells of brainstem tracts but was not overexpressed under hypoxia, although HIF‐1α mRNA was up‐regulated. In conclusion, there appear to be two regulatory mechanisms for HIF‐1α expression in the brainstem: hypoxic induction of HIF‐1α protein in cardiorespiratory‐related areas and constitutive protein expression unaffected by hypoxia in brainstem tracts.