Hypoxic pulmonary vasoconstriction: redox regulation of O2-sensitive K+ channels by a mitochondrial O2-sensor in resistance artery smooth muscle cells

Hypoxic pulmonary vasoconstriction (HPV) is a widely-conserved mechanism for matching ventilation and perfusion that optimizes systemic PO2. HPV is elicited by moderate alveolar hypoxia through a mechanism that is intrinsic to the pulmonary circulation, particularly the resistance pulmonary arteries (PA), and is robust even in isolated perfused lungs. Although modulated by the endothelium, HPV persists in denuded PA rings and PA smooth muscle cells (PASMC). Beginning within seconds of hypoxia, HPV plateaus in minutes and persists for hours. During focal hypoxia (e.g. atelectasis), HPV is restricted to the vascular segments serving hypoxic lobes, and diverts blood to better-ventilated segments without causing pulmonary hypertension (PHT). However, with global hypoxia, as occurs at high altitude or in the fetal lung, HPV increases pulmonary vascular resistance (PVR) and may contribute to PHT. This review focuses on a comprehensive Redox Theory of HPV but considers relevant modulatory factors (endothelin), triggering stimuli (cyclic ADP-ribose-induced release of sarcoplasmic reticulum (SR) Ca2+) and sustaining pathways (Rho kinase-modulated Ca2+ sensitization of the contractile apparatus). The Redox Theory proposes that an O2-sensor in resistance PASMC (complexes I and III of the mitochondrial electron transport chain (ETC)) generates reactive O2 species (ROS) in proportion to PO2. During normoxia, a redox mediator, like hydrogen peroxide (H2O2), maintains voltage-gated O2-sensitive K+ channels (Kv) in an oxidized open state. Hypoxic withdrawal of ROS inhibits Kv channels, thereby depolarizing PASMCs, activating L-type voltage-gated Ca2+ channels, enhancing Ca2+ influx and promoting vasoconstriction. The role of O2-sensitive K+ channels is conserved in most specialized O2-sensitive tissues, including the ductus arteriosus and carotid body. The unique occurrence of hypoxic vasoconstriction in the pulmonary circulation relates to the colocalization of an O2-sensor and O2-sensitive Kv channels in resistance PAs. HPV has relevance to human physiology, pathophysiology (high altitude pulmonary edema (HAPE) and PHT) and therapy (single lung anesthesia).