Hypoxic Pulmonary Vasoconstriction
Authors: James S.K. Sham
Journal: Circulation Research (2002)

eduction in alveolar oxygen tension causes reversible hypoxic pulmonary vasoconstriction (HPV), which is thought to serve as an adaptive mechanism for diverting blood flow from poorly ventilated to betterventilated regions of the lung to improve ventilationperfusion matching.Since first described by Von Euler and Liljestrand 1 50 years ago, significant advances have been made in determining the O 2 dependence, temporal characteristics, loci of response, physiological conditions, and neurohumoral factors that influence HPV in intact animal, isolated lung, and pulmonary arterial rings.Recent studies using isolated pulmonary arterial smooth muscle cells (PASMCs) indicate that hypoxia directly causes membrane depolarization, increase in intracellular [Ca 2ϩ ], and cell-shortening; thus, the essential elements of HPV are contained in PASMCs, even though one or more endothelially derived mediators, such as ET-1 and/or an unknown factor, 2,3 are required for the full expression of hypoxic response.However, despite this progress, the precise cellular mechanism of O 2 sensing for HPV remains controversial.There are several proposed mechanisms for O 2 sensing in PASMCs, most of which are related to reactive oxygen species (ROS). 4The first hypothesis proposed that a smooth muscle microsomal NADH oxidoreductase, which generates H 2 O 2 via a PO 2 -dependent production of superoxide, acts as the O 2 sensor; H 2 O 2 interacts with catalase to activate soluble guanylate cyclase and increase cGMP to provide tonic vasorelaxation during normoxia. 5,6Under hypoxic conditions, production of H 2 O 2 from NADH oxidase would be reduced, leading to the removal of the vasorelaxant influence, and pulmonary vasoconstriction.The second hypothesis proposed that hypoxia activates a sarcolemmal NADPH oxidase, similar to that found in neutrophils, to paradoxically increase superoxide production to signal HPV.This notion is supported by the evidence that NADPH oxidase was detected in pulmonary arteries by Western blot analysis and immunostaining of gp91 phox subunit, and by spectrometric analysis of cytochrome b Ϫ245 .Hypoxia was found to increase superoxide anion production, which was blocked by the inhibitor of NADPH oxidase, diphenyleneiodium (DPI), in cultured PASMCs. 7Moreover, DPI blocked hypoxic responses in isolated lung, isolated arteries, and PASMCs. 8,9However, the supporting evidence is weakened by the fact that DPI is a nonspecific blocker for many flavoprotein-dependent enzymes including complex I of the mitochondrial electron transport chain (ETC) and NO synthase (NOS), and other proteins such as K ϩ and Ca 2ϩ channels, and by the unaltered HPV in the phagocyte NADPH oxidase gp91 phox subunit knockout mice. 10,11he third hypothesis has received the most attention.It proposed a redox-based regulation of K V channel as the O 2 sensing mechanism for HPV. 12 According to this hypothesis, hypoxia reduces mitochondrial electron transport, decreases ROS generation, and shifts the ratio of redox couples (ie, GSSG:GSH and NAD ϩ :NADH) toward a more reduced state, leading to inhibition of K V channels, membrane depolarization, Ca 2ϩ influx via L-type Ca 2ϩ channels, increase in cytosolic [Ca 2ϩ ], and vasoconstriction.Consistent with this hypothesis, hypoxia or mitochondrial ETC inhibitors, rotenone and antimycin A, caused inhibition of K V current in PASMCs, vasoconstriction, and decreased luminol-enhanced chemiluminescence in isolated lungs, suggesting a decrease in ROS production. 12,13Agents that promoted cytosolic oxidation were reported to activate, whereas agents that promote cytosolic reduction caused inhibition of K V currents. 14However, the role of K V channel in initiating HPV has been questioned because an antagonist of K V channels failed to inhibit HPV, 2,15 and a functional sarcoplasmic reticulum (SR) was found to be required for HPV. 16Hence, it is proposed alternatively that K V channel inhibition during hypoxia is secondary to Ca 2ϩ release from SR. Beside K V channels, ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase may also act as redox sensors for HPV. 17A reduction of ␤-NAD ϩ :␤-NADH ratio during hypoxia was reported to stimulate ADP-ribosyl cyclase and inhibit cyclic ADP-ribose hydrolase, leading to accumulation of cyclic ADP-ribose, an endogenous activator of ryanodine receptors, to activate Ca 2ϩ release from SR.Recently, Waypa et al 18 proposed the fourth hypothesis of O 2 sensing.Using parallel experiments in isolated perfused lungs and PASMCs, they found that HPV was blocked by inhibitors acting at ETC sites proximal, but not distal, to superoxide production; mutant PASMCs lacking mitochondrial ETC failed to contract to hypoxia, whereas contraction to U46619 was unaffected.Moreover, 2Ј,7Ј-dichlorofluorescin diacetate (DCF) in PASMCs detected an increase in cytosolic ROS, which was blocked by myxothiazol, during hypoxia.Antioxidants and a Cu,Zn superoxide dismutase (SOD) inhibitor also blocked HPV.Based on these results, they proposed that mitochondria indeed function as O 2