Hypoxic pulmonary vasoconstriction.
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 Po(2). 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 O(2) species (ROS)] that regulates an effector protein [voltage-gated potassium (K(v)) and calcium channels]. A similar mechanism for regulating O(2) uptake/distribution is partially recapitulated in simpler organisms and in the other specialized mammalian O(2)-sensitive tissues, including the carotid body and ductus arteriosus. Inhibition of O(2)-sensitive K(v) channels, particularly K(v)1.5 and K(v)2.1, depolarizes pulmonary artery SMCs, activating voltage-gated Ca(2+) channels and causing Ca(2+) 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.
Moudgil
Rohit
R
Cardiology Division, Dept. of Medicine, and Vascular Biology Group, University of Alberta, WMC 2C2.36, 8440 112th Street, Edmonton, Alberta, Canada T6G 2B7.
Michelakis
Evangelos D
ED
Archer
Stephen L
SL
D000818:Animals; D006487:Hemostasis; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications / Q000503:physiopathology*; D008168:Lung / Q000503:physiopathology*; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014655:Vascular Resistance; D014661:Vasoconstriction
D017382:Reactive Oxygen Species; D010100:Oxygen