Physiology and Pathophysiology of Oxygen Sensitivity

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (15 April 2021) | Viewed by 26027

Special Issue Editors

Department of Biochemistry, Molecular Biology and Physiology, Institute of Molecular Biology and Genetics (IBGM), University of Valladolid-CSIC, Valladolid, Spain
Interests: oxygen sensing; carotid body; chemoreception; signalling pathways; hypoxia; intermittent hypoxia; neurotransmitters; reactive oxygen species; endothelial dysfunction
Special Issues, Collections and Topics in MDPI journals
Department of Inflammation Biology, School of Immunology and Microbial Sciences, King's College London, London, UK
Interests: oxygen sensing; hypoxic pulmonary vasoconstriction; reactive oxygen species; hydrogen sulphide; pulmonary hypertension
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Oxygen is such an essential element for life that multiple mechanisms have evolved to maintain oxygen homeostasis, including the ability of cells to detect and adapt to decreases in arterial O2. In mammals, O2 sensing mechanisms in erythropoietin-producing cells, peripheral chemoreceptor cells (carotid and aortic bodies), pulmonary artery smooth muscle and endothelial cells, chromaffin cells, and some types of neurons are particularly important in maintaining homeostasis.

Although acute O2 sensing by the carotid body (CB) and pulmonary vasculature initiates responses which allow the body to maintain adequate levels of blood oxygenation in the face of systemic hypoxemia and alveolar hypoxia, respectively, during chronic or long-term intermittent hypoxia, these responses evolve to become maladaptive. Continued CB stimulation leads to metabolic and cardiorespiratory disorders such as hypertension and heart failure, and sustained lung hypoxia causes pulmonary hypertension. Although much remains to be discovered about the mechanisms causing both the initial adaptive and subsequent deleterious responses to hypoxia, there is evidence from many laboratories for an essential role of oxidative stress at both stages. 

This Special Issue will include a selection of research papers and review articles related to O2 sensing and oxidative stress, physiological responses to acute or chronic hypoxia, and maladaptive responses to the hypoxic environment and their more recent translational implications. We are currently seeking to expand the content of the Issue and would welcome the submission of up-to-date review articles and experimental papers.

We dedicate this Special Issue to our colleagues who made important contributions to the field of chemoreception and particularly to our understanding of the CB and who have passed away in the last decade: Prof. Sukhamay Lahiri (2009), Prof. Constancio Gonzalez (2015), Prof. Machiko Shirahata (2016), and Prof. Chris Peers (2018). We may have lost them, but their legacy continues through the research of many scientific heirs, students, collaborators, and friends.

Prof. Dr. Asuncion Rocher
Dr. Philip I. Aaronson
Guest Editors

Manuscript Submission Information

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Keywords

  • oxygen sensing
  • acute and chronic hypoxia
  • chemoreception
  • carotid body
  • pulmonary artery smooth muscle cells
  • pulmonary artery endothelial cells
  • HIF-1
  • oxidative stress
  • chemosensory potentiation
  • hypoxic pulmonary vasoconstriction
  • pulmonary hypertension

Published Papers (10 papers)

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Editorial

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7 pages, 229 KiB  
Editorial
Oxygen Sensing: Physiology and Pathophysiology
Antioxidants 2022, 11(5), 1018; https://doi.org/10.3390/antiox11051018 - 21 May 2022
Cited by 1 | Viewed by 1506
Abstract
Oxygen is such an essential element for life that multiple mechanisms have evolved to maintain oxygen homeostasis, including those which detect decreases in arterial O2 and generate adaptive responses to hypoxia [...] Full article
(This article belongs to the Special Issue Physiology and Pathophysiology of Oxygen Sensitivity)

Research

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20 pages, 2507 KiB  
Article
Maladaptive Pulmonary Vascular Responses to Chronic Sustained and Chronic Intermittent Hypoxia in Rat
Antioxidants 2022, 11(1), 54; https://doi.org/10.3390/antiox11010054 - 27 Dec 2021
Cited by 5 | Viewed by 2634
Abstract
Chronic sustained hypoxia (CSH), as found in individuals living at a high altitude or in patients suffering respiratory disorders, initiates physiological adaptations such as carotid body stimulation to maintain oxygen levels, but has deleterious effects such as pulmonary hypertension (PH). Obstructive sleep apnea [...] Read more.
Chronic sustained hypoxia (CSH), as found in individuals living at a high altitude or in patients suffering respiratory disorders, initiates physiological adaptations such as carotid body stimulation to maintain oxygen levels, but has deleterious effects such as pulmonary hypertension (PH). Obstructive sleep apnea (OSA), a respiratory disorder of increasing prevalence, is characterized by a situation of chronic intermittent hypoxia (CIH). OSA is associated with the development of systemic hypertension and cardiovascular pathologies, due to carotid body and sympathetic overactivation. There is growing evidence that CIH can also compromise the pulmonary circulation, causing pulmonary hypertension in OSA patients and animal models. The aim of this work was to compare hemodynamics, vascular contractility, and L-arginine-NO metabolism in two models of PH in rats, associated with CSH and CIH exposure. We demonstrate that whereas CSH and CIH cause several common effects such as an increased hematocrit, weight loss, and an increase in pulmonary artery pressure (PAP), compared to CIH, CSH seems to have more of an effect on the pulmonary circulation, whereas the effects of CIH are apparently more targeted on the systemic circulation. The results suggest that the endothelial dysfunction evident in pulmonary arteries with both hypoxia protocols are not due to an increase in methylated arginines in these arteries, although an increase in plasma SDMA could contribute to the apparent loss of basal NO-dependent vasodilation and, therefore, the increase in PAP that results from CIH. Full article
(This article belongs to the Special Issue Physiology and Pathophysiology of Oxygen Sensitivity)
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22 pages, 3314 KiB  
Article
Aryl Hydrocarbon Receptor and Cysteine Redox Dynamics Underlie (Mal)adaptive Mechanisms to Chronic Intermittent Hypoxia in Kidney Cortex
Antioxidants 2021, 10(9), 1484; https://doi.org/10.3390/antiox10091484 - 17 Sep 2021
Cited by 6 | Viewed by 2796
Abstract
We hypothesized that an interplay between aryl hydrocarbon receptor (AhR) and cysteine-related thiolome at the kidney cortex underlies the mechanisms of (mal)adaptation to chronic intermittent hypoxia (CIH), promoting arterial hypertension (HTN). Using a rat model of CIH-HTN, we investigated the impact of short-term [...] Read more.
We hypothesized that an interplay between aryl hydrocarbon receptor (AhR) and cysteine-related thiolome at the kidney cortex underlies the mechanisms of (mal)adaptation to chronic intermittent hypoxia (CIH), promoting arterial hypertension (HTN). Using a rat model of CIH-HTN, we investigated the impact of short-term (1 and 7 days), mid-term (14 and 21 days, pre-HTN), and long-term intermittent hypoxia (IH) (up to 60 days, established HTN) on CYP1A1 protein level (a sensitive hallmark of AhR activation) and cysteine-related thiol pools. We found that acute and chronic IH had opposite effects on CYP1A1 and the thiolome. While short-term IH decreased CYP1A1 and increased protein-S-thiolation, long-term IH increased CYP1A1 and free oxidized cysteine. In addition, an in vitro administration of cystine, but not cysteine, to human endothelial cells increased Cyp1a1 expression, supporting cystine as a putative AhR activator. This study supports CYP1A1 as a biomarker of obstructive sleep apnea (OSA) severity and oxidized pools of cysteine as risk indicator of OSA-HTN. This work contributes to a better understanding of the mechanisms underlying the phenotype of OSA-HTN, mimicked by this model, which is in line with precision medicine challenges in OSA. Full article
(This article belongs to the Special Issue Physiology and Pathophysiology of Oxygen Sensitivity)
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17 pages, 4120 KiB  
Article
Chronic Intermittent Hypoxia Induces Early-Stage Metabolic Dysfunction Independently of Adipose Tissue Deregulation
Antioxidants 2021, 10(8), 1233; https://doi.org/10.3390/antiox10081233 - 30 Jul 2021
Cited by 5 | Viewed by 2512
Abstract
Several studies demonstrated a link between obstructive sleep apnea (OSA) and the development of insulin resistance. However, the main event triggering insulin resistance in OSA remains to be clarified. Herein, we investigated the effect of mild and severe chronic intermittent hypoxia (CIH) on [...] Read more.
Several studies demonstrated a link between obstructive sleep apnea (OSA) and the development of insulin resistance. However, the main event triggering insulin resistance in OSA remains to be clarified. Herein, we investigated the effect of mild and severe chronic intermittent hypoxia (CIH) on whole-body metabolic deregulation and visceral adipose tissue dysfunction. Moreover, we studied the contribution of obesity to CIH-induced dysmetabolic states. Experiments were performed in male Wistar rats submitted to a control and high-fat (HF) diet. Two CIH protocols were tested: A mild CIH paradigm (5/6 hypoxic (5% O2) cycles/h, 10.5 h/day) during 35 days and a severe CIH paradigm (30 hypoxic (5% O2) cycles, 8 h/day) during 15 days. Fasting glycemia, insulinemia, insulin sensitivity, weight, and fat mass were assessed. Adipose tissue hypoxia, inflammation, angiogenesis, oxidative stress, and metabolism were investigated. Mild and severe CIH increased insulin levels and induced whole-body insulin resistance in control animals, effects not associated with weight gain. In control animals, CIH did not modify adipocytes perimeter as well as adipose tissue hypoxia, angiogenesis, inflammation or oxidative stress. In HF animals, severe CIH attenuated the increase in adipocytes perimeter, adipose tissue hypoxia, angiogenesis, and dysmetabolism. In conclusion, adipose tissue dysfunction is not the main trigger for initial dysmetabolism in CIH. CIH in an early stage might have a protective role against the deleterious effects of HF diet on adipose tissue metabolism. Full article
(This article belongs to the Special Issue Physiology and Pathophysiology of Oxygen Sensitivity)
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19 pages, 2512 KiB  
Article
Mitochondrial Succinate Metabolism and Reactive Oxygen Species Are Important but Not Essential for Eliciting Carotid Body and Ventilatory Responses to Hypoxia in the Rat
Antioxidants 2021, 10(6), 840; https://doi.org/10.3390/antiox10060840 - 25 May 2021
Cited by 11 | Viewed by 2850
Abstract
Reflex increases in breathing in response to acute hypoxia are dependent on activation of the carotid body (CB)—A specialised peripheral chemoreceptor. Central to CB O2-sensing is their unique mitochondria but the link between mitochondrial inhibition and cellular stimulation is unresolved. The [...] Read more.
Reflex increases in breathing in response to acute hypoxia are dependent on activation of the carotid body (CB)—A specialised peripheral chemoreceptor. Central to CB O2-sensing is their unique mitochondria but the link between mitochondrial inhibition and cellular stimulation is unresolved. The objective of this study was to evaluate if ex vivo intact CB nerve activity and in vivo whole body ventilatory responses to hypoxia were modified by alterations in succinate metabolism and mitochondrial ROS (mitoROS) generation in the rat. Application of diethyl succinate (DESucc) caused concentration-dependent increases in chemoafferent frequency measuring approximately 10–30% of that induced by severe hypoxia. Inhibition of mitochondrial succinate metabolism by dimethyl malonate (DMM) evoked basal excitation and attenuated the rise in chemoafferent activity in hypoxia. However, approximately 50% of the response to hypoxia was preserved. MitoTEMPO (MitoT) and 10-(6′-plastoquinonyl) decyltriphenylphosphonium (SKQ1) (mitochondrial antioxidants) decreased chemoafferent activity in hypoxia by approximately 20–50%. In awake animals, MitoT and SKQ1 attenuated the rise in respiratory frequency during hypoxia, and SKQ1 also significantly blunted the overall hypoxic ventilatory response (HVR) by approximately 20%. Thus, whilst the data support a role for succinate and mitoROS in CB and whole body O2-sensing in the rat, they are not the sole mediators. Treatment of the CB with mitochondrial selective antioxidants may offer a new approach for treating CB-related cardiovascular–respiratory disorders. Full article
(This article belongs to the Special Issue Physiology and Pathophysiology of Oxygen Sensitivity)
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13 pages, 1269 KiB  
Article
Oxygen-Sensitivity and Pulmonary Selectivity of Vasodilators as Potential Drugs for Pulmonary Hypertension
Antioxidants 2021, 10(2), 155; https://doi.org/10.3390/antiox10020155 - 21 Jan 2021
Cited by 5 | Viewed by 1983
Abstract
Current approved therapies for pulmonary hypertension (PH) aim to restore the balance between endothelial mediators in the pulmonary circulation. These drugs may exert vasodilator effects on poorly oxygenated vessels. This may lead to the derivation of blood perfusion towards low ventilated alveoli, i.e., [...] Read more.
Current approved therapies for pulmonary hypertension (PH) aim to restore the balance between endothelial mediators in the pulmonary circulation. These drugs may exert vasodilator effects on poorly oxygenated vessels. This may lead to the derivation of blood perfusion towards low ventilated alveoli, i.e., producing ventilation-perfusion mismatch, with detrimental effects on gas exchange. The aim of this study is to analyze the oxygen-sensitivity in vitro of 25 drugs currently used or potentially useful for PH. Additionally, the study analyses the effectiveness of these vasodilators in the pulmonary vs. the systemic vessels. Vasodilator responses were recorded in pulmonary arteries (PA) and mesenteric arteries (MA) from rats and in human PA in a wire myograph under different oxygen concentrations. None of the studied drugs showed oxygen selectivity, being equally or more effective as vasodilators under conditions of low oxygen as compared to high oxygen levels. The drugs studied showed low pulmonary selectivity, being equally or more effective as vasodilators in systemic than in PA. A similar behavior was observed for the members within each drug family. In conclusion, none of the drugs showed optimal vasodilator profile, which may limit their therapeutic efficacy in PH. Full article
(This article belongs to the Special Issue Physiology and Pathophysiology of Oxygen Sensitivity)
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Review

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30 pages, 3672 KiB  
Review
A Case for Hydrogen Sulfide Metabolism as an Oxygen Sensing Mechanism
Antioxidants 2021, 10(11), 1650; https://doi.org/10.3390/antiox10111650 - 21 Oct 2021
Cited by 19 | Viewed by 2839
Abstract
The ability to detect oxygen availability is a ubiquitous attribute of aerobic organisms. However, the mechanism(s) that transduce oxygen concentration or availability into appropriate physiological responses is less clear and often controversial. This review will make the case for oxygen-dependent metabolism of hydrogen [...] Read more.
The ability to detect oxygen availability is a ubiquitous attribute of aerobic organisms. However, the mechanism(s) that transduce oxygen concentration or availability into appropriate physiological responses is less clear and often controversial. This review will make the case for oxygen-dependent metabolism of hydrogen sulfide (H2S) and polysulfides, collectively referred to as reactive sulfur species (RSS) as a physiologically relevant O2 sensing mechanism. This hypothesis is based on observations that H2S and RSS metabolism is inversely correlated with O2 tension, exogenous H2S elicits physiological responses identical to those produced by hypoxia, factors that affect H2S production or catabolism also affect tissue responses to hypoxia, and that RSS efficiently regulate downstream effectors of the hypoxic response in a manner consistent with a decrease in O2. H2S-mediated O2 sensing is then compared to the more generally accepted reactive oxygen species (ROS) mediated O2 sensing mechanism and a number of reasons are offered to resolve some of the confusion between the two. Full article
(This article belongs to the Special Issue Physiology and Pathophysiology of Oxygen Sensitivity)
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14 pages, 984 KiB  
Review
Oxygen Biosensors and Control in 3D Physiomimetic Experimental Models
Antioxidants 2021, 10(8), 1165; https://doi.org/10.3390/antiox10081165 - 22 Jul 2021
Cited by 6 | Viewed by 2654
Abstract
Traditional cell culture is experiencing a revolution moving toward physiomimetic approaches aiming to reproduce healthy and pathological cell environments as realistically as possible. There is increasing evidence demonstrating that biophysical and biochemical factors determine cell behavior, in some cases considerably. Alongside the explosion [...] Read more.
Traditional cell culture is experiencing a revolution moving toward physiomimetic approaches aiming to reproduce healthy and pathological cell environments as realistically as possible. There is increasing evidence demonstrating that biophysical and biochemical factors determine cell behavior, in some cases considerably. Alongside the explosion of these novel experimental approaches, different bioengineering techniques have been developed and improved. Increased affordability and popularization of 3D bioprinting, fabrication of custom-made lab-on-a chip, development of organoids and the availability of versatile hydrogels are factors facilitating the design of tissue-specific physiomimetic in vitro models. However, lower oxygen diffusion in 3D culture is still a critical limitation in most of these studies, requiring further efforts in the field of physiology and tissue engineering and regenerative medicine. During recent years, novel advanced 3D devices are introducing integrated biosensors capable of monitoring oxygen consumption, pH and cell metabolism. These biosensors seem to be a promising solution to better control the oxygen delivery to cells and to reproduce some disease conditions involving hypoxia. This review discusses the current advances on oxygen biosensors and control in 3D physiomimetic experimental models. Full article
(This article belongs to the Special Issue Physiology and Pathophysiology of Oxygen Sensitivity)
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20 pages, 429 KiB  
Review
Sex Dimorphism in Pulmonary Hypertension: The Role of the Sex Chromosomes
Antioxidants 2021, 10(5), 779; https://doi.org/10.3390/antiox10050779 - 14 May 2021
Cited by 9 | Viewed by 3627
Abstract
Pulmonary hypertension (PH) is a condition characterised by an abnormal elevation of pulmonary artery pressure caused by an increased pulmonary vascular resistance, frequently leading to right ventricular failure and reduced survival. Marked sexual dimorphism is observed in patients with pulmonary arterial hypertension, a [...] Read more.
Pulmonary hypertension (PH) is a condition characterised by an abnormal elevation of pulmonary artery pressure caused by an increased pulmonary vascular resistance, frequently leading to right ventricular failure and reduced survival. Marked sexual dimorphism is observed in patients with pulmonary arterial hypertension, a form of pulmonary hypertension with a particularly severe clinical course. The incidence in females is 2–4 times greater than in males, although the disease is less severe in females. We review the contribution of the sex chromosomes to this sex dimorphism highlighting the impact of proteins, microRNAs and long non-coding RNAs encoded on the X and Y chromosomes. These genes are centrally involved in the cellular pathways that cause increased pulmonary vascular resistance including the production of reactive oxygen species, altered metabolism, apoptosis, inflammation, vasoconstriction and vascular remodelling. The interaction with genetic mutations on autosomal genes that cause heritable pulmonary arterial hypertension such as bone morphogenetic protein 2 (BMPR2) are examined. The mechanisms that can lead to differences in the expression of genes located on the X chromosomes between females and males are also reviewed. A better understanding of the mechanisms of sex dimorphism in this disease will contribute to the development of more effective therapies for both women and men. Full article
(This article belongs to the Special Issue Physiology and Pathophysiology of Oxygen Sensitivity)
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Other

4 pages, 367 KiB  
Opinion
Physiology and Pathophysiology of Oxygen Sensitivity
Antioxidants 2021, 10(7), 1114; https://doi.org/10.3390/antiox10071114 - 12 Jul 2021
Cited by 4 | Viewed by 1531
Abstract
Oxygen is an essential requirement for metabolism in mammals and many other animals. Therefore, pathways that sense a reduction in available oxygen are critical for organism survival. Higher mammals developed specialized organs to detect and respond to changes in O2 content to [...] Read more.
Oxygen is an essential requirement for metabolism in mammals and many other animals. Therefore, pathways that sense a reduction in available oxygen are critical for organism survival. Higher mammals developed specialized organs to detect and respond to changes in O2 content to maintain gas homeostasis by balancing oxygen demand and supply. Here, we summarize the various oxygen sensors that have been identified in mammals (carotid body, aortic bodies, and astrocytes), by what mechanisms they detect oxygen and the cellular and molecular aspects of their function on control of respiratory and circulatory O2 transport that contribute to maintaining normal physiology. Finally, we discuss how dysregulation of oxygen availability leads to elevated signalling sensitivity in these systems and may contribute to the pathogenesis of chronic cardiovascular and respiratory diseases and many other disorders. Hence, too little oxygen, too much oxygen, and a malfunctioning sensitivity of receptors/sensors can create major pathophysiological problems for the organism. Full article
(This article belongs to the Special Issue Physiology and Pathophysiology of Oxygen Sensitivity)
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