HYPOXIC INTENSITY REVEALS DISTINCT CAROTID BODY O2 SENSING MECHANISMS.

Abstract

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.