This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 91/6/478    most recent 01.RES.0000035057.63303.D1v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Michelakis, E. D. Articles by Archer, S. L. Search for Related Content PubMed PubMed Citation Articles by Michelakis, E. D. Articles by Archer, S. L. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB 4-AMINOPYRIDINE OXYGEN Related Collections Remodeling Ion channels/membrane transport Pulmonary biology and circulation Pulmonary circulation and disease Other Vascular biology

(Circulation Research. 2002;91:478.)
© 2002 American Heart Association, Inc.

Integrative Physiology

O₂ Sensing in the Human Ductus Arteriosus

Regulation of Voltage-Gated K⁺ Channels in Smooth Muscle Cells by a Mitochondrial Redox Sensor

Evangelos D. Michelakis, Ivan Rebeyka, XiChen Wu, Ali Nsair, Bernard Thébaud, Kyoko Hashimoto, Jason R.B. Dyck, Al Haromy, Gwyneth Harry, Amy Barr, Stephen L. Archer

From the Cardiology Division and the Vascular Biology Group, Department of Medicine (E.D.M., X.W., A.N., B.T., K.H., J.R.B.D., A.H., G.H., S.L.A.), the Division of Cardiac Surgery (I.R.), the Cardiovascular Research Group (A.B.), and the Department of Physiology (S.L.A.), University of Alberta, Alberta, Canada.

Correspondence to Stephen L. Archer, MD, Heart and Stroke Chair in Cardiovascular Research, Chair, Cardiology Division, Dept of Medicine, University of Alberta, WMC 2C2.36, 8440 112th St, Edmonton, Alberta, Canada T6G 2B7. E-mail sarcher{at}cha.ab.ca

Functional closure of the human ductus arteriosus (DA) is initiated within minutes of birth by O₂ constriction. It occurs by an incompletely understood mechanism that is intrinsic to the DA smooth muscle cell (DASMC). We hypothesized that O₂ alters the function of an O₂ sensor (the mitochondrial electron transport chain, ETC) thereby increasing production of a diffusible redox-mediator (H₂O₂), thus triggering an effector mechanism (inhibition of DASMC voltage-gated K⁺ channels, Kv). O₂ constriction was evaluated in 26 human DAs (12 female, aged 9±2 days) studied in their normal hypoxic state or after normoxic tissue culture. In fresh, hypoxic DAs, 4-aminopyridine (4-AP), a Kv inhibitor, and O₂ cause similar constriction and K⁺ current inhibition (I_K). Tissue culture for 72 hours, particularly in normoxia, causes ionic remodeling, characterized by decreased O₂ and 4-AP constriction in DA rings and reduced O₂- and 4-AP–sensitive I_K in DASMCs. Remodeled DAMSCs are depolarized and express less O₂-sensitive channels (including Kv2.1, Kv1.5, Kv9.3, Kv4.3, and BK_Ca). Kv2.1 adenoviral gene-transfer significantly reverses ionic remodeling, partially restoring both the electrophysiological and tone responses to 4-AP and O₂. In fresh DASMCs, ETC inhibitors (rotenone and antimycin) mimic hypoxia, increasing I_K and reversing constriction to O₂, but not phenylephrine. O₂ increases, whereas hypoxia and ETC inhibitors decrease H₂O₂ production by altering mitochondrial membrane potential (m). H₂O₂, like O₂, inhibits I_K and depolarizes DASMCs. We conclude that O₂ controls human DA tone by modulating the function of the mitochondrial ETC thereby varying m and the production of H₂O₂, which regulates DASMC Kv channel activity and DA tone.

Key Words: Kv2.1 • Kv1.5 • mitochondrial membrane potential • redox • hydrogen peroxide

This article has been cited by other articles:

				A. L. Cogolludo, J. Moral-Sanz, S. van der Sterren, G. Frazziano, A. N. H. van Cleef, C. Menendez, B. Zoer, E. Moreno, A. Roman, F. Perez-Vizcaino, et al. Maturation of O2 sensing and signaling in the chicken ductus arteriosus Am J Physiol Lung Cell Mol Physiol, October 1, 2009; 297(4): L619 - L630. [Abstract] [Full Text] [PDF]

				A. L. Firth, D. V. Gordienko, K. H. Yuill, and S. V. Smirnov Cellular localization of mitochondria contributes to Kv channel-mediated regulation of cellular excitability in pulmonary but not mesenteric circulation Am J Physiol Lung Cell Mol Physiol, March 1, 2009; 296(3): L347 - L360. [Abstract] [Full Text] [PDF]

				H. Greyner and E. M. Dzialowski Mechanisms mediating the oxygen-induced vasoreactivity of the ductus arteriosus in the chicken embryo Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2008; 295(5): R1647 - R1659. [Abstract] [Full Text] [PDF]

				A. L. Firth, K. H. Yuill, and S. V. Smirnov Mitochondria-dependent regulation of Kv currents in rat pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, July 1, 2008; 295(1): L61 - L70. [Abstract] [Full Text] [PDF]

				E. L. Bell, T. A. Klimova, J. Eisenbart, P. T. Schumacker, and N. S. Chandel Mitochondrial Reactive Oxygen Species Trigger Hypoxia-Inducible Factor-Dependent Extension of the Replicative Life Span during Hypoxia Mol. Cell. Biol., August 15, 2007; 27(16): 5737 - 5745. [Abstract] [Full Text] [PDF]

				H. Kajimoto, K. Hashimoto, S. N. Bonnet, A. Haromy, G. Harry, R. Moudgil, T. Nakanishi, I. Rebeyka, B. Thebaud, E. D. Michelakis, et al. Oxygen Activates the Rho/Rho-Kinase Pathway and Induces RhoB and ROCK-1 Expression in Human and Rabbit Ductus Arteriosus by Increasing Mitochondria-Derived Reactive Oxygen Species: A Newly Recognized Mechanism for Sustaining Ductal Constriction Circulation, April 3, 2007; 115(13): 1777 - 1788. [Abstract] [Full Text] [PDF]

				P. Agren, A. L. Cogolludo, C. G. A. Kessels, F. Perez-Vizcaino, J. G. R. De Mey, C. E. Blanco, and E. Villamor Ontogeny of chicken ductus arteriosus response to oxygen and vasoconstrictors Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2007; 292(1): R485 - R496. [Abstract] [Full Text] [PDF]

				G. Sutendra and E. D. Michelakis The chicken embryo as a model for ductus arteriosus developmental biology: cracking into new territory Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2007; 292(1): R481 - R484. [Full Text] [PDF]

				E. K. Weir and S. L. Archer COUNTERPOINT: HYPOXIC PULMONARY VASOCONSTRICTION IS NOT MEDIATED BY INCREASED PRODUCTION OF REACTIVE OXYGEN SPECIES J Appl Physiol, September 1, 2006; 101(3): 995 - 998. [Full Text] [PDF]

				N. Weissmann, N. Sommer, R. T. Schermuly, H. A. Ghofrani, W. Seeger, and F. Grimminger Oxygen sensors in hypoxic pulmonary vasoconstriction Cardiovasc Res, September 1, 2006; 71(4): 620 - 629. [Abstract] [Full Text] [PDF]

				E. K. Weir and A. Olschewski Role of ion channels in acute and chronic responses of the pulmonary vasculature to hypoxia Cardiovasc Res, September 1, 2006; 71(4): 630 - 641. [Abstract] [Full Text] [PDF]

				M. Costa, S. Barogi, N. D. Socci, D. Angeloni, M. Maffei, B. Baragatti, C. Chiellini, E. Grasso, and F. Coceani Gene expression in ductus arteriosus and aorta: comparison of birth and oxygen effects Physiol Genomics, April 13, 2006; 25(2): 250 - 262. [Abstract] [Full Text] [PDF]

				E. K. Weir, J. Lopez-Barneo, K. J. Buckler, and S. L. Archer Acute Oxygen-Sensing Mechanisms. N. Engl. J. Med., November 10, 2005; 353(19): 2042 - 2055. [Full Text] [PDF]

				B. Thebaud, F. Ladha, E. D. Michelakis, M. Sawicka, G. Thurston, F. Eaton, K. Hashimoto, G. Harry, A. Haromy, G. Korbutt, et al. Vascular Endothelial Growth Factor Gene Therapy Increases Survival, Promotes Lung Angiogenesis, and Prevents Alveolar Damage in Hyperoxia-Induced Lung Injury: Evidence That Angiogenesis Participates in Alveolarization Circulation, October 18, 2005; 112(16): 2477 - 2486. [Abstract] [Full Text] [PDF]

				L. C. Hool, C. A. Di Maria, H. M. Viola, and P. G. Arthur Role of NAD(P)H oxidase in the regulation of cardiac L-type Ca2+ channel function during acute hypoxia Cardiovasc Res, September 1, 2005; 67(4): 624 - 635. [Abstract] [Full Text] [PDF]

				J. Wang, L. Weigand, W. Wang, J. T. Sylvester, and L. A. Shimoda Chronic hypoxia inhibits Kv channel gene expression in rat distal pulmonary artery Am J Physiol Lung Cell Mol Physiol, June 1, 2005; 288(6): L1049 - L1058. [Abstract] [Full Text] [PDF]

				D. D. Gutterman, H. Miura, and Y. Liu Redox Modulation of Vascular Tone: Focus of Potassium Channel Mechanisms of Dilation Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 671 - 678. [Abstract] [Full Text] [PDF]

				S. M. Tipparaju, N. Saxena, S.-Q. Liu, R. Kumar, and A. Bhatnagar Differential regulation of voltage-gated K+ channels by oxidized and reduced pyridine nucleotide coenzymes Am J Physiol Cell Physiol, February 1, 2005; 288(2): C366 - C376. [Abstract] [Full Text] [PDF]

				R. Moudgil, E. D. Michelakis, and S. L. Archer Hypoxic pulmonary vasoconstriction J Appl Physiol, January 1, 2005; 98(1): 390 - 403. [Abstract] [Full Text] [PDF]

				B. Thebaud, E. D. Michelakis, X.-C. Wu, R. Moudgil, M. Kuzyk, J. R.B. Dyck, G. Harry, K. Hashimoto, A. Haromy, I. Rebeyka, et al. Oxygen-Sensitive Kv Channel Gene Transfer Confers Oxygen Responsiveness to Preterm Rabbit and Remodeled Human Ductus Arteriosus: Implications for Infants With Patent Ductus Arteriosus Circulation, September 14, 2004; 110(11): 1372 - 1379. [Abstract] [Full Text] [PDF]

				F. S. GRAGASIN, E. D. MICHELAKIS, A. HOGAN, R. MOUDGIL, K. HASHIMOTO, X. WU, S. BONNET, A. HAROMY, and S. L. ARCHER The neurovascular mechanism of clitoral erection: nitric oxide and cGMP-stimulated activation of BKCa channels FASEB J, September 1, 2004; 18(12): 1382 - 1391. [Abstract] [Full Text] [PDF]

				S. L. Archer, X.-C. Wu, B. Thebaud, A. Nsair, S. Bonnet, B. Tyrrell, M. S. McMurtry, K. Hashimoto, G. Harry, and E. D. Michelakis Preferential Expression and Function of Voltage-Gated, O2-Sensitive K+ Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction: Ionic Diversity in Smooth Muscle Cells Circ. Res., August 6, 2004; 95(3): 308 - 318. [Abstract] [Full Text] [PDF]

				S. J. Fountain, A. Cheong, R. Flemming, L. Mair, A. Sivaprasadarao, and D. J. Beech Functional up-regulation of KCNA gene family expression in murine mesenteric resistance artery smooth muscle J. Physiol., April 1, 2004; 556(1): 29 - 42. [Abstract] [Full Text] [PDF]

				Z. I. Pozeg, E. D. Michelakis, M. S. McMurtry, B. Thebaud, X.-C. Wu, J. R.B. Dyck, K. Hashimoto, S. Wang, R. Moudgil, G. Harry, et al. In Vivo Gene Transfer of the O2-Sensitive Potassium Channel Kv1.5 Reduces Pulmonary Hypertension and Restores Hypoxic Pulmonary Vasoconstriction in Chronically Hypoxic Rats Circulation, April 22, 2003; 107(15): 2037 - 2044. [Abstract] [Full Text] [PDF]

				S. L. Archer, F. S. Gragasin, X. Wu, S. Wang, S. McMurtry, D. H. Kim, M. Platonov, A. Koshal, K. Hashimoto, W. B. Campbell, et al. Endothelium-Derived Hyperpolarizing Factor in Human Internal Mammary Artery Is 11,12-Epoxyeicosatrienoic Acid and Causes Relaxation by Activating Smooth Muscle BKCa Channels Circulation, February 11, 2003; 107(5): 769 - 776. [Abstract] [Full Text] [PDF]