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A mitochondrial redox oxygen sensor in the pulmonary vasculature and ductus arteriosus

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Abstract

The mammalian homeostatic oxygen sensing system (HOSS) initiates changes in vascular tone, respiration, and neurosecretion that optimize oxygen uptake and tissue oxygen delivery within seconds of detecting altered environmental or arterial PO2. The HOSS includes carotid body type 1 cells, adrenomedullary cells, neuroepithelial bodies, and smooth muscle cells (SMCs) in pulmonary arteries (PAs), ductus arteriosus (DA), and fetoplacental arteries. Hypoxic pulmonary vasoconstriction (HPV) optimizes ventilation–perfusion matching. In utero, HPV diverts placentally oxygenated blood from the non-ventilated lung through the DA. At birth, increased alveolar and arterial oxygen tension dilates the pulmonary vasculature and constricts the DA, respectively, thereby transitioning the newborn to an air-breathing organism. Though modulated by endothelial-derived relaxing and constricting factors, O2 sensing is intrinsic to PASMCs and DASMCs. Within the SMC’s dynamic mitochondrial network, changes in PO2 alter the reduction–oxidation state of redox couples (NAD+/NADH, NADP+/NADPH) and the production of reactive oxygen species, ROS (e.g., H2O2), by complexes I and III of the electron transport chain (ETC). ROS and redox couples regulate ion channels, transporters, and enzymes, changing intracellular calcium [Ca2+]i and calcium sensitivity and eliciting homeostatic responses to hypoxia. In PASMCs, hypoxia inhibits ROS production and reduces redox couples, thereby inhibiting O2-sensitive voltage-gated potassium (Kv) channels, depolarizing the plasma membrane, activating voltage-gated calcium channels (CaL), increasing [Ca2+]i, and causing vasoconstriction. In DASMCs, elevated PO2 causes mitochondrial fission, increasing ETC complex I activity and ROS production. The DASMC’s downstream response to elevated PO2 (Kv channel inhibition, CaL activation, increased [Ca2+]i, and rho kinase activation) is similar to the PASMC’s hypoxic response. Impaired O2 sensing contributes to human diseases, including pulmonary arterial hypertension and patent DA.

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Funding sources

This work is supported by the National Institutes of Health RO1-HL071115 and 1RC1HL099462, Canadian Institutes for Health Research Foundation Award 333058, the Canada Foundation for Innovation (CFI) 33518 and 229252, the William J Henderson Foundation, and a Canada Research Chair 229252 (SLA).

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Authors and Affiliations

  1. Department of Medicine, Queen’s University, Etherington Hall, Room 3041, 94 Stuart St, Kingston, ON, K7L 3N6, Canada

    Kimberly J. Dunham-Snary, Zhigang G. Hong, Ping Y. Xiong, Joseph C. Del Paggio, Julia E. Herr, Amer M. Johri & Stephen L. Archer

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  1. Kimberly J. Dunham-Snary
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  2. Zhigang G. Hong
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  3. Ping Y. Xiong
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  4. Joseph C. Del Paggio
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  5. Julia E. Herr
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  6. Amer M. Johri
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  7. Stephen L. Archer
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Correspondence to Stephen L. Archer.

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This article is published as part of the Special Issue on Ion Channels and Sensors in Oxygen Adaptation

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Dunham-Snary, K.J., Hong, Z.G., Xiong, P.Y. et al. A mitochondrial redox oxygen sensor in the pulmonary vasculature and ductus arteriosus. Pflugers Arch - Eur J Physiol 468, 43–58 (2016). https://doi.org/10.1007/s00424-015-1736-y

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  • DOI: https://doi.org/10.1007/s00424-015-1736-y

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