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INVITED REVIEW
HIGHLIGHTED TOPICS
Pulmonary Circulation and Hypoxia
Department of Medicine (Cardiology) and the Vascular Biology Group, University of Alberta, Alberta, Canada
Humans encounter hypoxia throughout their lives. This occurs by destiny in utero, through disease, and by desire, in our quest for altitude. Hypoxic pulmonary vasoconstriction (HPV) is a widely conserved, homeostatic, vasomotor response of resistance pulmonary arteries to alveolar hypoxia. HPV mediates ventilation-perfusion matching and, by reducing shunt fraction, optimizes systemic PO2. HPV is intrinsic to the lung, and, although modulated by the endothelium, the core mechanism is in the smooth muscle cell (SMC). The Redox Theory for the mechanism of HPV proposes the coordinated action of a redox sensor (the proximal mitochondrial electron transport chain) that generates a diffusible mediator [a reactive O2 species (ROS)] that regulates an effector protein [voltage-gated potassium (Kv) and calcium channels]. A similar mechanism for regulating O2 uptake/distribution is partially recapitulated in simpler organisms and in the other specialized mammalian O2-sensitive tissues, including the carotid body and ductus arteriosus. Inhibition of O2-sensitive Kv channels, particularly Kv1.5 and Kv2.1, depolarizes pulmonary artery SMCs, activating voltage-gated Ca2+ channels and causing Ca2+ influx and vasoconstriction. Downstream of this pathway, there is important regulation of the contractile apparatus' sensitivity to calcium by rho kinase. Controversy remains as to whether hypoxia decreases or increases ROS and which electron transport chain complex generates the ROS (I and/or III). Possible roles for cyclic adenosine diphosphate ribose and an unidentified endothelial constricting factor are also proposed by some groups. Modulation of HPV has therapeutic relevance to cor pulmonale, high-altitude pulmonary edema, and sleep apnea. HPV is clinically exploited in single-lung anesthesia, and its mechanisms intersect with those of pulmonary arterial hypertension.
rho kinase; endothelin; cyclic adenosine 5'-diphosphate ribose; oxygen sensing; voltage-gated potassium channels; pulmonary hypertension; cor pulmonale; mitochondrial electron transport chain; redox; reactive oxygen species
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