Mutual antagonism between hypoxia-inducible factors 1α and 2α regulates oxygen sensing and cardio-respiratory homeostasis

Significance The carotid body (CB) chemosensory reflex and catecholamine secretion by the adrenal medulla (AM) are principal regulators of cardio-respiratory function during hypoxia, but the molecular mechanisms by which the CB and AM respond to hypoxia with changes in breathing and blood pressure are unknown. Hypoxia-inducible factor-1 (HIF-1) and HIF-2 mediate adaptive transcriptional responses to hypoxia. Herein, we demonstrate that a mutual functional antagonism between HIF-1 and HIF-2 plays a critical role in O2 sensing by establishing a dynamic balance that determines the proper redox set point in the CB and AM, which is essential for maintenance of cardio-respiratory homeostasis. Breathing and blood pressure are under constant homeostatic regulation to maintain optimal oxygen delivery to the tissues. Chemosensory reflexes initiated by the carotid body and catecholamine secretion from the adrenal medulla are the principal mechanisms for maintaining respiratory and cardiovascular homeostasis; however, the underlying molecular mechanisms are not known. Here, we report that balanced activity of hypoxia-inducible factor-1 (HIF-1) and HIF-2 is critical for oxygen sensing by the carotid body and adrenal medulla, and for their control of cardio-respiratory function. In Hif2α+/− mice, partial HIF-2α deficiency increased levels of HIF-1α and NADPH oxidase 2, leading to an oxidized intracellular redox state, exaggerated hypoxic sensitivity, and cardio-respiratory abnormalities, which were reversed by treatment with a HIF-1α inhibitor or a superoxide anion scavenger. Conversely, in Hif1α+/− mice, partial HIF-1α deficiency increased levels of HIF-2α and superoxide dismutase 2, leading to a reduced intracellular redox state, blunted oxygen sensing, and impaired carotid body and ventilatory responses to chronic hypoxia, which were corrected by treatment with a HIF-2α inhibitor. None of the abnormalities observed in Hif1α+/− mice or Hif2α+/− mice were observed in Hif1α+/−;Hif2α+/− mice. These observations demonstrate that redox balance, which is determined by mutual antagonism between HIF-α isoforms, establishes the set point for hypoxic sensing by the carotid body and adrenal medulla, and is required for maintenance of cardio-respiratory homeostasis.