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• W2110411622 abstract "RespirationEditorial Focus: Oxygen sensors and mediators of the contractile responses of smooth muscle to hypoxia. Focus on: “Hydrogen sulfide mediates hypoxic vasoconstriction through a production of mitochondrial ROS in trout gills”Jose F. Perez-ZoghbiJose F. Perez-ZoghbiDepartment of Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, TexasPublished Online:01 Sep 2012https://doi.org/10.1152/ajpregu.00327.2012This is the final version - click for previous versionMoreSectionsPDF (63 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat smooth muscle cells (smcs) in vascular and other tissues reversibly change their tone in response to acute variations in oxygen tension, and this results in important physiological and pathophysiological responses of the organ or system. The best studied example includes the changes in blood vessel diameter in response to decreases in oxygen tension (hypoxia). Thus, in response to tissue hypoxia, systemic peripheral arteries normally dilate, thereby increasing oxygen delivery into the tissue. Conversely, in the lung, hypoxia constricts the pulmonary arteries—a response called hypoxic pulmonary vasoconstriction (HPV), which can have either beneficial effects, by reducing and diverting blood flow from poor ventilated regions in the lung and thus optimizing ventilation-perfusion matching and gas exchange, or detrimental effects by increasing pulmonary vascular resistance, resulting in pulmonary hypertension at high altitude or during lung disease (3). In addition, the SMCs in other systems also respond to changes in oxygen tension. For example in the lung, the airways relax in response to hypoxia (7), which also may have a role in ventilation-perfusion matching by facilitating ventilation of hypoxic alveoli.Despite previous research efforts, the mechanisms of hypoxia-induced changes in SMC tone are still incompletely understood. Several proposed mechanisms and controversy in the field are summarized in a recent excellent review (8). A first step in the recognition of the hypoxia stimulus is sensing the oxygen level in the tissue or bloodstream; there appears to be consensus in that the cell that senses the oxygen level is the SMC itself. However, several questions remain unanswered: What are the oxygen-sensing molecules? Where are the sensors located in the cell? How do these sensors sense the oxygen level change?Recently, the group led by Kenneth Olson at Indiana University School of Medicine has proposed a revolutionary hypothesis that, if confirmed, may help to find the answers to the above questions. This hypothesis suggests that a new gasotransmitter, hydrogen sulfide (H2S) (9) may be an early mediator of the contractile responses of vascular SMCs to hypoxia (1, 4). The accumulated evidence that support this proposition have been summarized in recent reviews (5, 9) and include the following observations: 1) H2S is synthesized by cells in the blood vessels; its synthesis is stimulated during hypoxia, and the H2S concentration is affected by oxygen level via multiple mechanisms, including oxygen-regulated enzymatic production in the cytosol and oxygen-dependent consumption in mitochondria; 2) the vascular responses to hypoxia and H2S of a given blood vessel, either systemic or pulmonary (including the blood vessels in gills) are virtually identical in many vertebrate species, from cows to lamprey, irrespective of whether the effect is relaxation, constriction, or a complex response, 3) the responses to hypoxia and H2S are competitive in that maximal stimulation with one prevents a response to the other; 4) the sulfur donor, cysteine, augments the response to hypoxia; and 5) inhibitors of H2S biosynthesis also inhibit the responses to hypoxia. Together, the accumulated evidence strongly suggests that H2S is an early mediator of the hypoxic responses of blood vessels, whereas the oxygen sensor must be located in one or multiple molecules responsible for the regulation of H2S concentration in the cells of the blood vessels.In this issue, Skovgaard and Olson (6) now report a detailed comparative study of the vascular effects of hypoxia and H2S in trout gills that provides further evidence that H2S is a mediator of the hypoxic response of respiratory vasculature. They found that both hypoxia and H2S trigger vasoconstriction in the gills, both fast and transient. The responses triggered by hypoxia and H2S had similar magnitudes and kinetics, were not additive, and were mutually exclusive in that prestimulation with one stimulus inhibited the effect of the other stimulus. The hypoxia-induced vasoconstrictor was blocked by inhibitors of H2S synthesis. These results confirm the hypothesis that H2S is an early mediator of the vascular response to hypoxia. In addition, the response to H2S, as well as to hypoxia, was abolished by inhibition of the mitochondrial electron transport systems. Furthermore, the responses to hypoxia and H2S were inhibited by the antioxidant and superoxide scavenger glutathione, whereas hydrogen peroxide (H2O2) triggered similar contractile responses in nonstimulated gills. These last two findings are very important since it allows the authors to propose that H2S mediates hypoxic vasoconstriction in trout gills through the production of reactive oxygen species (ROS) by the mitochondria and H2O2 generation. This important conclusion links H2S to the well-supported role of ROS and H2O2 in the mediation of the vascular responses to hypoxia (3, 8).In conclusion, the new findings presented by Skovgaard and Olson (6) in this issue support a new hypothesis that proposes that endogenous H2S is an early mediator of the responses of vascular SMCs to hypoxia that is upstream of mitochondrial ROS production and H2O2 generation. Finally, it is possible that in other SMCs that respond to hypoxia, H2S may be as well the early mediator of the responses to hypoxia. For example, airway SMCs are relaxed by both hypoxia (7) and H2S (2), and it will be interesting to learn whether both responses have similar kinetics and pharmacological properties, and whether they are mutually exclusive. Thus, we can look forward to other studies that will test this novel hypothesis in vascular and other SMC types, as well as in other cells and tissues that respond to hypoxia.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author.AUTHOR CONTRIBUTIONSAuthor contributions: J.F.P.-Z. drafted manuscript; J.F.P.-Z. edited and revised manuscript; J.F.P.-Z. approved final version of manuscript.REFERENCES1. Dombkowski RA , Doellman MM , Head SK , Olson KR. Hydrogen sulfide mediates hypoxia-induced relaxation of trout urinary bladder smooth muscle. J Exp Biol 209: 3234–3240, 2006.Crossref | PubMed | ISI | Google Scholar2. Kubo S , Doe I , Kurokawa Y , Kawabata A. Hydrogen sulfide causes relaxation in mouse bronchial smooth muscle. J Pharm Sci 104: 392–396, 2007.Crossref | PubMed | ISI | Google Scholar3. Moudgil R , Michelakis ED , Archer SL. Hypoxic pulmonary vasoconstriction. J Appl Physiol 98: 390–403, 2005.Link | ISI | Google Scholar4. Olson KR , Dombkowski RA , Russell MJ , Doellman MM , Head SK , Whitfield NL , Madden JA. Hydrogen sulfide as an oxygen sensor/transducer in vertebrate hypoxic vasoconstriction and hypoxic vasodilation. J Exp Biol 209: 4011–4023, 2006.Crossref | PubMed | ISI | Google Scholar5. Olson KR , Donald JA , Dombkowski RA , Perry SF. Evolutionary and comparative aspects of nitric oxide, carbon monoxide and hydrogen sulfide. Respir Physiol Neurobiol In press.ISI | Google Scholar6. Skovgaard N , Olson KR. Hydrogen sulfide mediates hypoxic vasoconstriction through a production of mitochondrial ROS in trout gills. Am J Physiol Regul Integr Comp Physiol (June 27, 2012). doi: 10.1152/ajpregu.00151.2012.Link | ISI | Google Scholar7. Stephens NL , Kroeger E. Effect of hypoxia on airway smooth muscle mechanics and electrophysiology. J Appl Physiol 28: 630–635, 1970.Link | ISI | Google Scholar8. Sylvester JT , Shimoda LA , Aaronson PI , Ward JP. Hypoxic pulmonary vasoconstriction. Physiol Rev 92: 367–520, 2012.Link | ISI | Google Scholar9. Wang R. Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev 92: 791–896, 2012.Link | ISI | Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Collections Cited ByExogenous H2S facilitating ubiquitin aggregates clearance via autophagy attenuates type 2 diabetes-induced cardiomyopathy10 August 2017 | Cell Death & Disease, Vol. 8, No. 8 More from this issue > Volume 303Issue 5September 2012Pages R485-R486 Copyright & PermissionsCopyright © 2012 the American Physiological Societyhttps://doi.org/10.1152/ajpregu.00327.2012PubMed22814672History Received 17 July 2012 Accepted 18 July 2012 Published online 1 September 2012 Published in print 1 September 2012 Metrics" @default.
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