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POINT-COUNTERPOINT
1Department of Medicine
Veterans Affairs Medical Center;
2University of Minnesota
Minneapolis, Minnesota
e-mail: weirx002{at}umn.edu;
3Department of Medicine
University of Alberta
Edmonton, Alberta, Canada
The acute hypoxic pulmonary vasoconstriction (HPV) that we discuss in this debate involves rapid constriction of small pulmonary arteries in response to physiological levels of alveolar hypoxia. HPV starts within seconds of the onset of hypoxic ventilation and we focus on the early events before changes in gene expression are involved. Hypoxia causes contraction of pulmonary artery smooth muscle cells (PASMCs) directly (12), although this contraction is modulated by the endothelium.
Most scientists working in the field of HPV would probably agree on three components of the executive part of HPV. These are: hypoxic inhibition of potassium channels with consequent membrane depolarization and calcium entry through L-type calcium channels, release of calcium from the sarcoplasmic reticulum with subsequent entry of calcium through store-operated channels (SOC), and increased sensitivity of actin/myosin to any particular level of calcium, mediated by increased activity of rho kinase (23). Different researchers will emphasize the importance of particular components differently but the element involving potassium channels is present not only in the pulmonary vasculature but also in the other oxygen-sensing tissues that comprise the mammalian "specialized oxygen homeostatic system" (the carotid body, the neuroepithelial body, and fetal adrenomedullary chromaffin cells). If we agree, more or less, on the executive arm, what is the disagreement on the sensing mechanism that initiates executive action? Our opponent has to convince the discerning audience that "HPV is mediated by increased production of reactive oxygen species" (ROS). To win the hearts and minds of our esteemed readers (and the debate), we only have to show that the balance of evidence favors the aggregate of all the other hypotheses of the mechanism of oxygen sensing that signals HPV. Thus if ROS are more likely to decrease with hypoxia (2) or to stay the same; if HPV is signaled by a change in redox couples (e.g., NAD(P)H/NADP, GSH/GSSG; Ref. 22); by a direct effect of oxygen (comparable to its interaction with prolyl hydroxylase in the destruction of HIF1
; Ref. 13); by a shift in high energy phosphates (e.g., AMP/ATP ratio; Ref. 8); by an H2O2-dependent fall in cGMP (7); or by a change in carbon monoxide (25), we win the debate. We have proposed over the last 20 years that HPV is signaled by a decrease in ROS or by more reduced redox couples (2, 4, 22). So we will focus on two questions, does a decrease in ROS occur in hypoxia and does such a decrease cause pulmonary vasoconstriction?
The predominant sources of ROS in PASMCs are the mitochondria and NADPH oxidase. In the mitochondria throughout the cytoplasm, ROS are produced by electrons that traverse the ETC in an uncoupled manner (<5%), largely at complexes I and III. The superoxide is rapidly changed to H2O2 by superoxide dismutase 2 (SOD2), an intramitochondrial antioxidant enzyme. H2O2 diffuses to the membrane and alters the gating of membrane K+ channels (such that more H2O2 opens the channels and less, as occurs in hypoxia, closes the channel-causing depolarization and HPV) (Fig. 2). It is generally accepted that ROS production goes up in hyperoxia, in lung homogenates (9), mitochondria (21), and endothelial cells (6). Our opponent says that ROS levels also go up when oxygen levels go down. If the production of ROS is a U-shaped function with an increase above and below "normoxic" levels of oxygen, then hyperoxia should cause vasoconstriction in a manner similar to HPV. However, acute hyperoxic pulmonary vasoconstriction is not observed in dogs when the inspired oxygen is increased to 30 or 100%; in fact pulmonary artery (PA) pressure and resistance decreases progressively (20). Nor is hyperoxic pulmonary hypertension observed clinically in the many patients given supplementary oxygen. There is considerable evidence that ROS go down during hypoxia in the lungs (2, 18, 24), PA denuded of endothelium (3, 14), and PA endothelial cells (26, 28, 29). These studies used four different ways to measure a fall of ROS during hypoxia in four different species.
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We explored the intersection of oxygen sensing and pulmonary arterial hypertension (PAH) in Fawn-Hooded rats (FHR), a mutant strain that spontaneously develops PAH after age 20 wk and, despite normal PO2, behaves as if it was chronically hypoxic [polycythemia, decreased O2-sensitive, voltage-gated (Kv) channels in PASMCs, decreased HPV; Ref. 5]. Their impaired O2 sensing is associated with decreased ROS formation, leading to activation of HIF-1. The loss of ROS relates to a newly recognized defect in the PASMC mitochondria. The FHR's mitochondrial network is disrupted and their mitochondria are dysmorphic, hyperpolarized, deficient in electron transport complexes I and IV (cytochrome oxidase) and SOD2, and make fewer ROS. This occurs before onset of PAH. The ROS that are made are relatively insensitive to rotenone and hypoxia, consistent with the selective loss of HPV and rotenone constriction. This causes normoxic HIF-1 activation and decreases Kv1.5, Kv3.1b expression. The mitochondrial dysfunction and loss of ROS appears mechanically relevant to both the loss of HPV and onset of PAH because dichloracetate, which normalizes mitochondrial function, inactivates HIF, restores Kv expression, and improves survival. The mitochondrial abnormalities and HIF-1 activation, are recapitulated in human PAH.
There are a number of other experiments in several oxygen-sensitive tissues where the functional effect of oxygen can be prevented by the use of catalase to remove H2O2 or electron transport chain inhibitors to prevent the formation of O2–/H2O2 (e.g., diphenyliodonium, DPI). Catalase prevents PA relaxation in response to oxygen (7). In porcine PA endothelial cells hypoxia decreases ROS production and increases the G-protein RhoA. Both effects are reproduced by DPI (27). In the neuroepithelial body, as in the PA, hypoxia and DPI inhibit potassium current, which can be increased by H2O2 (10). Similarly, in the H-146 small cell lung carcinoma line, hypoxia reduces ROS and inhibits potassium current, which is increased by H2O2 (16). These studies show that H2O2 mimicks oxygen, not hypoxia, in a variety of oxygen-sensitive tissues in the lung.
The strongest support for our position comes from our opponent who states, "Currently, the best documented hypothesis for HPV proposes that Ca2+ entry is mediated primarily via voltage-dependent L-type channels ... Kv channel inhibition is caused by a decrease in the ambient intracellular concentration of H2O2 which results when mitochondrial electron transport, and consequently the production of superoxide ion, falls due to the lack of O2. There is an enormous body of evidence supporting this hypothesis ..." (1). We rest our case.
GRANTS
E. K. Weir is supported by VA Merit Review Funding and NHLBI Grant ROI-HL-65322. Dr. Archer is Heart and Stroke Chair in Cardiovascular Research and Canada Research Chair (CRC) in Oxygen-Sensing and Translational Cardiovascular Research. He is supported by NIH-RO1-HL07115, the Canada Foundation for Innovation, the Alberta Heart and Stroke Foundation, the Canadian Institutes for Health Research (CIHR), and the Alberta Cardiovascular and Stroke Research Centre (ABACUS).
REFERENCES
-Kv channel pathway disrupts oxygen-sensing and triggers pulmonary arterial hypertension (PAH) in fawn-hooded rats: similarities to human PAH. Circulation. In press.This article has been cited by other articles:
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  J. P. Mehta, J. L. Campian, J. Guardiola, J. A. Cabrera, E. K. Weir, and J. W. Eaton Generation of Oxidants by Hypoxic Human Pulmonary and Coronary Smooth-Muscle Cells Chest, June 1, 2008; 133(6): 1410 - 1414. [Abstract] [Full Text] [PDF]
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 N. Weissmann Hypoxia-driven mechanisms in lung biology and disease: a new review series of the ERS Lung Science Conference Eur. Respir. J., April 1, 2008; 31(4): 697 - 698. [Full Text] [PDF]
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 S. L. Archer, M. Gomberg-Maitland, M. L. Maitland, S. Rich, J. G. N. Garcia, and E. K. Weir Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1{alpha}-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H570 - H578. [Abstract] [Full Text] [PDF]
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 G. B. Waypa and P. T. Schumacker Oxygen sensing in hypoxic pulmonary vasoconstriction: using new tools to answer an age-old question Exp Physiol, January 1, 2008; 93(1): 133 - 138. [Abstract] [Full Text] [PDF]
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 W. Wu, O. Platoshyn, A. L. Firth, and J. X.-J. Yuan Hypoxia divergently regulates production of reactive oxygen species in human pulmonary and coronary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, October 1, 2007; 293(4): L952 - L959. [Abstract] [Full Text] [PDF]
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