HYPOXIC INTENSITY REVEALS DISTINCT CAROTID BODY O2 SENSING MECHANISMS.

Carotid bodies (CBs) sense arterial blood O2 levels. Hypoxemia activates the carotid sinus nerve (CSN) afferent activity to elicit cardiorespiratory reflexes to maintain tissue oxygenation. This brief review presents emerging evidence suggesting that CBs employ distinct O2-sensing mechanisms depending on the severity of hypoxia. During physiologically relevant moderate hypoxia (pO2 ~40 mmHg), glomus cells use heme oxygenase-2 (HO-2)/carbon monoxide (CO)/cystathionine-γ-lyase (CSE)/hydrogen sulfide (H2S) signaling pathway to stimulate CSN activity and breathing response to hypoxia. Basal CO restrains CSN activity during normoxia, whereas hypoxia reduces CO and stimulates CSN activity through H2S. Olfactory receptor 78 (Olfr78) is required for H2S-mediated CSN activation. CO-H2S pathway contributes to cardiorespiratory physiological adaptations to sustained hypoxia and to the pathophysiology of diseases characterized by carotid body (CB) hyperactivity. In contrast, glomus cell responds to severe hypoxia (pO2 ~5-15 mmHg) through mitochondrial complex I (NDUFS2) and complex III. Thus, CBs appear to employ severity-dependent hypoxic sensing mechanisms wherein moderate hypoxia engages the CO-H2S pathway to activate CSN activity and drive homeostatic cardiorespiratory responses. Severe hypoxia primarily alters mitochondrial function and glomus cell metabolism. Physiological relevance of severe-hypoxia remains uncertain, because severe low O2 levels suppresses both CB, CSN activity and ventilation.