Regulation of carotid body oxygen sensing by hypoxia-inducible factors

Oxygen (O-2) sensing by the carotid body and its chemosensory reflex is critical for homeostatic regulation of breathing and blood pressure. Carotid body responses to hypoxia are not uniform but instead exhibit remarkable inter-individual variations. The molecular mechanisms underlying variations in carotid body O-2 sensing are not known. Hypoxia-inducible factor-1 (HIF-1) and HIF-2 mediate transcriptional responses to hypoxia. This article reviews the emerging evidence that proper expression of the HIF-alpha isoforms is a key molecular determinant for carotid body O-2 sensing. HIF-1 alpha deficiency leads to a blunted carotid body hypoxic response, which is due to increased abundance of HIF-2 alpha, elevated anti-oxidant enzyme activity, and a reduced intracellular redox state. Conversely, HIF-2 alpha deficiency results in augmented carotid body sensitivity to hypoxia, which is due to increased abundance of HIF-1 alpha, elevated pro-oxidant enzyme activity, and an oxidized intracellular redox state. Double heterozygous mice with equally reduced HIF-1 alpha and HIF-2 alpha showed no abnormality in redox state or carotid body O-2 sensing. Thus, mutual antagonism between HIF-alpha isoforms determines the redox state and thereby establishes the set point for hypoxic sensing by the carotid body.