{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T17:26:42Z","timestamp":1789838802634,"version":"4.0.1"},"reference-count":104,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T00:00:00Z","timestamp":1660003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"RUK Cambridge Centre","award":["C9685\/A23214"],"award-info":[{"award-number":["C9685\/A23214"]}]},{"name":"School of Medicine, Dentistry and Biomedical Sciences, Queen\u2019s University, Belfast","award":["C9685\/A23214"],"award-info":[{"award-number":["C9685\/A23214"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Organ function relies on microvascular networks to maintain homeostatic equilibrium, which varies widely in different organs and during different physiological challenges. The endothelium role in this critical process can only be evaluated in physiologically relevant contexts. Comparing the responses to oxygen flux in primary murine microvascular EC (MVEC) obtained from brain and lung tissue reveals that supra-physiological oxygen tensions can compromise MVEC viability. Brain MVEC lose mitochondrial activity and undergo significant alterations in electron transport chain (ETC) composition when cultured under standard, non-physiological atmospheric oxygen levels. While glycolytic capacity of both lung and brain MVEC are unchanged by environmental oxygen, the ability to trigger a metabolic shift when oxygen levels drop is greatly compromised following exposure to hyperoxia. This is particularly striking in MVEC from the brain. This work demonstrates that the unique metabolism and function of organ-specific MVEC (1) can be reprogrammed by external oxygen, (2) that this reprogramming can compromise MVEC survival and, importantly, (3) that ex vivo modelling of endothelial function is significantly affected by culture conditions. It further demonstrates that physiological, metabolic and functional studies performed in non-physiological environments do not represent cell function in situ, and this has serious implications in the interpretation of cell-based pre-clinical models.<\/jats:p>","DOI":"10.3390\/cells11162469","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T02:42:53Z","timestamp":1660099373000},"page":"2469","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Hyperoxia Reprogrammes Microvascular Endothelial Cell Response to Hypoxia in an Organ-Specific Manner"],"prefix":"10.3390","volume":"11","author":[{"given":"Moritz","family":"Reiterer","sequence":"first","affiliation":[{"name":"Patrick G Johnston Centre for Cancer Research, Queen\u2019s University, Belfast BT9 7AE, UK"},{"name":"Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Eakin","sequence":"additional","affiliation":[{"name":"Patrick G Johnston Centre for Cancer Research, Queen\u2019s University, Belfast BT9 7AE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randall S.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6953-4922","authenticated-orcid":false,"given":"Cristina M.","family":"Branco","sequence":"additional","affiliation":[{"name":"Patrick G Johnston Centre for Cancer Research, Queen\u2019s University, Belfast BT9 7AE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"eaal2379","DOI":"10.1126\/science.aal2379","article-title":"Organotypic vasculature: From descriptive heterogeneity to functional pathophysiology","volume":"357","author":"Augustin","year":"2017","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1161\/01.RES.0000255691.76142.4a","article-title":"Phenotypic Heterogeneity of the Endothelium","volume":"100","author":"Aird","year":"2007","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1111\/febs.15143","article-title":"Endothelial cells and organ function: Applications and implications of understanding unique and reciprocal remodelling","volume":"287","author":"Reiterer","year":"2020","journal-title":"FEBS J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/j.cmet.2020.05.004","article-title":"Endothelial Lactate Controls Muscle Regeneration from Ischemia by Inducing M2-like Macrophage Polarization","volume":"31","author":"Zhang","year":"2020","journal-title":"Cell Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.devcel.2013.06.017","article-title":"Molecular Signatures of Tissue-Specific Microvascular Endothelial Cell Heterogeneity in Organ Maintenance and Regeneration","volume":"26","author":"Nolan","year":"2013","journal-title":"Dev. Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/nature09493","article-title":"Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration","volume":"468","author":"Ding","year":"2010","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.cell.2011.10.003","article-title":"Endothelial-Derived Angiocrine Signals Induce and Sustain Regenerative Lung Alveolarization","volume":"147","author":"Ding","year":"2011","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1136\/thoraxjnl-2017-210598","article-title":"Reference values for oxygen saturation from sea level to the highest human habitation in the Andes in acclimatised persons","volume":"73","author":"Mejia","year":"2018","journal-title":"Thorax"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"47","DOI":"10.2165\/00007256-200030010-00005","article-title":"Exercise-Induced Arterial Hypoxaemia in Athletes","volume":"30","author":"Prefaut","year":"2000","journal-title":"Sports Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1056\/NEJMra0910283","article-title":"Hypoxia and inflammation","volume":"364","author":"Eltzschig","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"R611","DOI":"10.1152\/ajpregu.00182.2017","article-title":"Red blood cell antibody-induced anemia causes differential degrees of tissue hypoxia in kidney and brain","volume":"314","author":"Mistry","year":"2018","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1007\/s00109-007-0281-3","article-title":"Hypoxia and cancer","volume":"85","author":"Chiche","year":"2007","journal-title":"J. Mol. Med. (Berl.)"},{"key":"ref_13","first-page":"199","article-title":"Hypoxemia in patients with COPD: Cause, effects, and disease progression","volume":"6","author":"Kent","year":"2011","journal-title":"Int J. Chron. Obs. Pulmon Dis."},{"key":"ref_14","first-page":"2983","article-title":"Endothelial MMP14 is required for endothelial-dependent growth support of human airway basal cells","volume":"128","author":"Ding","year":"2015","journal-title":"J. Cell Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1038\/sj.eye.6700133","article-title":"The pathogenesis of diabetic retinopathy: Old concepts and new questions","volume":"16","author":"Cai","year":"2002","journal-title":"Eye (Lond.)"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1161\/CIRCRESAHA.115.306301","article-title":"Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis","volume":"118","author":"Gimbrone","year":"2016","journal-title":"Circ. Res."},{"key":"ref_17","first-page":"260482","article-title":"Consequences of Hyperoxia and the Toxicity of Oxygen in the Lung","volume":"2011","author":"Mach","year":"2011","journal-title":"Nurs. Res. Pract."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1152\/ajpregu.00165.2017","article-title":"Highs and lows of hyperoxia: Physiological, performance, and clinical aspects","volume":"315","author":"Brugniaux","year":"2018","journal-title":"Am. J. Physiol.-Regul. Integr. Comp. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"606678","DOI":"10.3389\/fmed.2021.606678","article-title":"Hyperoxia and Lungs: What We Have Learned From Animal Models","volume":"8","author":"Amarelle","year":"2021","journal-title":"Front. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1097\/00006123-199811000-00045","article-title":"Clinical Experience with 118 Brain Tissue Oxygen Partial Pressure Catheter Probes","volume":"43","author":"Dings","year":"1998","journal-title":"Neurosurgery"},{"key":"ref_21","first-page":"1","article-title":"Partial pressure of oxygen in the human body: A general review","volume":"9","author":"Dunn","year":"2019","journal-title":"Am. J. Blood Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1038\/s42255-019-0105-0","article-title":"Oxygen and mammalian cell culture: Are we repeating the experiment of Dr. Ox?","volume":"1","author":"Ast","year":"2019","journal-title":"Nat. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"20130676","DOI":"10.1259\/bjr.20130676","article-title":"Defining normoxia, physoxia and hypoxia in tumours\u2014implications for treatment response","volume":"87","author":"McKeown","year":"2014","journal-title":"Br. J. Radiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.cell.2012.01.021","article-title":"Hypoxia-inducible factors in physiology and medicine","volume":"148","author":"Semenza","year":"2012","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e288","DOI":"10.1016\/S1473-3099(16)30402-9","article-title":"New WHO recommendations on intraoperative and postoperative measures for surgical site infection prevention: An evidence-based global perspective","volume":"16","author":"Allegranzi","year":"2016","journal-title":"Lancet Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1001\/archsurg.1997.01430330063010","article-title":"Wound Tissue Oxygen Tension Predicts the Risk of Wound Infection in Surgical Patients","volume":"132","author":"Hopf","year":"1997","journal-title":"Arch. Surg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1177\/088506668900400204","article-title":"Analytic Reviews: Hyperbaric Oxygen Therapy","volume":"4","author":"Thom","year":"1989","journal-title":"J. Intensive Care Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.pmrj.2009.03.012","article-title":"Hyperbaric Oxygen Therapy for Wound Healing and Limb Salvage: A Systematic Review","volume":"1","author":"Goldman","year":"2009","journal-title":"PMR"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1185\/03007995.2015.1082988","article-title":"Radiotherapy after hyperbaric oxygenation in malignant gliomas","volume":"31","author":"Chen","year":"2015","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1111\/j.1524-475X.2010.00660.x","article-title":"Vasculogenic stem cell mobilization and wound recruitment in diabetic patients: Increased cell number and intracellular regulatory protein content associated with hyperbaric oxygen therapy","volume":"19","author":"Thom","year":"2011","journal-title":"Wound Repair Regen."},{"key":"ref_31","first-page":"202","article-title":"Oxygen toxicity seizures: 20 years\u2019 experience from a single hyperbaric unit","volume":"41","author":"Banham","year":"2011","journal-title":"Diving Hyperb. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1083\/jcb.32.3.605","article-title":"Development of Fine Structural Damage to Alveolar and Capillary Lining Cells in Oxygen-Poisoned Rat Lungs","volume":"32","author":"Kistler","year":"1967","journal-title":"J. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"16317","DOI":"10.1074\/jbc.M313890200","article-title":"Extracellular ATP-mediated signaling for survival in hyperoxia-induced oxidative stress","volume":"279","author":"Ahmad","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_34","first-page":"L411","article-title":"Synergistic cytotoxicity from nitric oxide and hyperoxia in cultured lung cells","volume":"274","author":"Narula","year":"1998","journal-title":"Am. J. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1038\/labinvest.3700281","article-title":"Mouse syngenic in vitro blood\u2013brain barrier model: A new tool to examine inflammatory events in cerebral endothelium","volume":"85","author":"Coisne","year":"2005","journal-title":"Lab. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Watson, P.M.D., Paterson, J.C., Thom, G., Ginman, U., Lundquist, S., and Webster, C.I. (2013). Modelling the endothelial blood-CNS barriers: A method for the production of robust in vitromodels of the rat blood-brain barrier and blood-spinal cord barrier. BMC Neurosci., 14.","DOI":"10.1186\/1471-2202-14-59"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Ruck, T., Bittner, S., Epping, L., Herrmann, A.M., and Meuth, S.G. (2014). Isolation of Primary Murine Brain Microvascular Endothelial Cells. J. Vis. Exp., e52204.","DOI":"10.3791\/52204"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Welser-Alves, J.V., Boroujerdi, A., and Milner, R. (2014). Isolation and Culture of Primary Mouse Brain Endothelial Cells. Methods Mol. Biol., 345\u2013356.","DOI":"10.1007\/978-1-4939-0320-7_28"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1073\/pnas.86.2.695","article-title":"Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites","volume":"86","author":"Casals","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1177\/37.2.2463300","article-title":"Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: Evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein","volume":"37","author":"Thiebaut","year":"1989","journal-title":"J. Histochem. Cytochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.ccr.2011.11.017","article-title":"Endothelial Cell HIF-1\u03b1 and HIF-2\u03b1 Differentially Regulate Metastatic Success","volume":"21","author":"Zhang","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1002\/mrm.20423","article-title":"3D volume-localizedpO2 measurement in the human lung with3He MRI","volume":"53","author":"Wild","year":"2005","journal-title":"Magn. Reson. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.placenta.2004.07.002","article-title":"Dissolved oxygen concentration in culture medium: Assumptions and pitfalls","volume":"26","author":"Newby","year":"2005","journal-title":"Placenta"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1089\/adt.2015.669","article-title":"Bioluminescent, Nonlytic, Real-Time Cell Viability Assay and Use in Inhibitor Screening","volume":"13","author":"Duellman","year":"2015","journal-title":"Assay Drug Dev. Technol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"14871","DOI":"10.1074\/jbc.M400461200","article-title":"Prolonged Hypoxia Differentially Regulates Hypoxia-inducible Factor (HIF)-1\u03b1 and HIF-2\u03b1 Expression in Lung Epithelial Cells","volume":"279","author":"Uchida","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7929","DOI":"10.1096\/fj.201802650RR","article-title":"Primary endothelial cell\u2013specific regulation of hypoxia-inducible factor (HIF)-1 and HIF-2 and their target gene expression profiles during hypoxia","volume":"33","author":"Bartoszewski","year":"2019","journal-title":"FASEB J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1038\/s41598-020-58616-0","article-title":"Author Correction: Acute and chronic hypoxia differentially predispose lungs for metastases","volume":"10","author":"Reiterer","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"C1541","DOI":"10.1152\/ajpcell.00068.2010","article-title":"Hypoxic upregulation of arginase II in human lung endothelial cells","volume":"299","author":"Krotova","year":"2010","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.1128\/MCB.00166-09","article-title":"Hypoxia-Induced Autophagy Is Mediated through Hypoxia-Inducible Factor Induction of BNIP3 and BNIP3L via Their BH3 Domains","volume":"29","author":"Bellot","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Liu, K.E., and Frazier, W.A. (2015). Phosphorylation of the BNIP3 C-Terminus Inhibits Mitochondrial Damage and Cell Death without Blocking Autophagy. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0129667"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrc3183","article-title":"HIF1\u03b1 and HIF2\u03b1: Sibling rivalry in hypoxic tumour growth and progression","volume":"12","author":"Keith","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_52","first-page":"136","article-title":"Changes of oxygen tension in brain and somatic tissues induced by vasodilator and vasoconstrictor drugs","volume":"155","author":"Cater","year":"1961","journal-title":"Proc. R. Soc. London. Ser. B. Biol. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/0026-2862(77)90088-7","article-title":"The oxygen tension field within a discrete volume of cerebral cortex","volume":"13","author":"Smith","year":"1977","journal-title":"Microvasc. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"35","DOI":"10.2147\/HP.S92198","article-title":"Frequently asked questions in hypoxia research","volume":"3","author":"Wenger","year":"2015","journal-title":"Hypoxia"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1101\/sqb.2011.76.010678","article-title":"Regulation of Metabolism by Hypoxia-Inducible Factor 1","volume":"76","author":"Semenza","year":"2011","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1095\/biolreprod.113.108225","article-title":"Transcriptional and Functional Adaptations of Human Endothelial Cells to Physiological Chronic Low Oxygen1","volume":"88","author":"Jiang","year":"2013","journal-title":"Biol. Reprod."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Chen, Y., and Gaber, T. (2021). Hypoxia\/HIF Modulates Immune Responses. Biomedicines, 9.","DOI":"10.3390\/biomedicines9030260"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.1101\/gad.924501","article-title":"FIH-1: A novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity","volume":"15","author":"Mahon","year":"2001","journal-title":"Genes Dev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1101\/gad.991402","article-title":"FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor","volume":"16","author":"Lando","year":"2002","journal-title":"Genes Dev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"cm8","DOI":"10.1126\/stke.4072007cm8","article-title":"Hypoxia-inducible factor 1 (HIF-1) pathway","volume":"2007","author":"Semenza","year":"2007","journal-title":"Sci STKE"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.cmet.2017.10.005","article-title":"Advances in Hypoxia-Inducible Factor Biology","volume":"27","author":"Choudhry","year":"2018","journal-title":"Cell Metab."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Corrado, C., and Fontana, S. (2020). Hypoxia and HIF Signaling: One Axis with Divergent Effects. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21165611"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.cmet.2019.08.011","article-title":"Hallmarks of Endothelial Cell Metabolism in Health and Disease","volume":"30","author":"Li","year":"2019","journal-title":"Cell Metab."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/B978-0-12-416618-9.00005-4","article-title":"Techniques to monitor glycolysis","volume":"542","author":"TeSlaa","year":"2014","journal-title":"Methods Enzym."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/jid.2012.267","article-title":"Toll-like receptor 4 has an essential role in early skin wound healing","volume":"133","author":"Chen","year":"2013","journal-title":"J. Investig. Derm."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1016\/j.cmet.2018.02.020","article-title":"The Factor Inhibiting HIF Asparaginyl Hydroxylase Regulates Oxidative Metabolism and Accelerates Metabolic Adaptation to Hypoxia","volume":"27","author":"Sim","year":"2018","journal-title":"Cell Metab."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.tibs.2012.06.004","article-title":"Passing the baton: The HIF switch","volume":"37","author":"Koh","year":"2012","journal-title":"Trends Biochem. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1161\/ATVBAHA.114.304277","article-title":"Laminar Shear Stress Inhibits Endothelial Cell Metabolism via KLF2-Mediated Repression of PFKFB3","volume":"35","author":"Doddaballapur","year":"2015","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.cmet.2013.08.001","article-title":"Role of Endothelial Cell Metabolism in Vessel Sprouting","volume":"18","author":"Georgiadou","year":"2013","journal-title":"Cell Metab."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.15252\/embj.201696150","article-title":"Endothelial cell metabolism in health and disease: Impact of hypoxia","volume":"36","author":"Wong","year":"2017","journal-title":"EMBO J."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1161\/CIRCRESAHA.119.316463","article-title":"Role of the GLUT1 Glucose Transporter in Postnatal CNS Angiogenesis and Blood-Brain Barrier Integrity","volume":"127","author":"Veys","year":"2020","journal-title":"Circ. Res."},{"key":"ref_72","first-page":"71","article-title":"Brain glucose transporters: Relationship to local energy demand","volume":"16","author":"Duelli","year":"2001","journal-title":"News Physiol. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"17478","DOI":"10.1073\/pnas.1209281109","article-title":"Normal glucose uptake in the brain and heart requires an endothelial cell-specific HIF-1 -dependent function","volume":"109","author":"Huang","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"109375","DOI":"10.1016\/j.mehy.2019.109375","article-title":"Hyperbaric oxygen toxicity in brain: A case of hyperoxia induced hypoglycemic brain syndrome","volume":"132","author":"Wilson","year":"2019","journal-title":"Med. Hypotheses"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1002\/ana.410010502","article-title":"The large apparent work capability of the blood-brain barrier: A study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat","volume":"1","author":"Oldendorf","year":"1977","journal-title":"Ann. Neurol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"101152","DOI":"10.1016\/j.redox.2019.101152","article-title":"O(2) affects mitochondrial functionality ex vivo","volume":"22","author":"Nanadikar","year":"2019","journal-title":"Redox Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.celrep.2017.09.026","article-title":"AMPK Maintains Cellular Metabolic Homeostasis through Regulation of Mitochondrial Reactive Oxygen Species","volume":"21","author":"Rabinovitch","year":"2017","journal-title":"Cell Rep."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1113\/JP275852","article-title":"Sensors and signals: The role of reactive oxygen species in hypoxic pulmonary vasoconstriction","volume":"597","author":"Smith","year":"2019","journal-title":"J. Physiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.bbabio.2013.01.004","article-title":"Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning","volume":"1827","year":"2013","journal-title":"Biochim. Biophys. Acta (BBA)-Bioenerg."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"BSR20171492","DOI":"10.1042\/BSR20171492","article-title":"Insights into the respiratory chain and oxidative stress","volume":"38","author":"Larosa","year":"2018","journal-title":"Biosci. Rep."},{"key":"ref_81","first-page":"3","article-title":"Mitochondrial electron transport chain, ROS generation and uncoupling (Review)","volume":"44","author":"Zhao","year":"2019","journal-title":"Int. J. Mol. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1249\/MSS.0000000000000563","article-title":"Reactive Oxygen Species, Mitochondria, and Endothelial Cell Death during In Vitro Simulated Dives","volume":"47","author":"Wang","year":"2015","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1161\/STROKEAHA.115.009099","article-title":"Mitochondrial crisis in cerebrovascular endothelial cells opens the blood-brain barrier","volume":"46","author":"Doll","year":"2015","journal-title":"Stroke"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1177\/0271678X15606147","article-title":"MiR-34a regulates blood-brain barrier permeability and mitochondrial function by targeting cytochrome c","volume":"36","author":"Bukeirat","year":"2016","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Rellick, S.L., Hu, H., Simpkins, J.W., and Ren, X. (2016). Evaluation of Bioenergetic Function in Cerebral Vascular Endothelial Cells. J. Vis. Exp., 54847.","DOI":"10.3791\/54847"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1016\/j.bbabio.2016.03.012","article-title":"Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis","volume":"1857","author":"Tretter","year":"2016","journal-title":"Biochim. Biophys. Acta (BBA)-Bioenerg."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.cell.2016.08.064","article-title":"Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages","volume":"167","author":"Mills","year":"2016","journal-title":"Cell"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1093\/hmg\/ddx041","article-title":"Mitochondrial complex II regulates a distinct oxygen sensing mechanism in monocytes","volume":"26","author":"Sharma","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.ymgme.2020.09.009","article-title":"The genetic basis of isolated mitochondrial complex II deficiency","volume":"131","author":"Fullerton","year":"2020","journal-title":"Mol. Genet. Metab"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"e1835","DOI":"10.1038\/cddis.2015.202","article-title":"Mitochondrial complex II is a source of the reserve respiratory capacity that is regulated by metabolic sensors and promotes cell survival","volume":"6","author":"Pfleger","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1161\/ATVBAHA.117.310605","article-title":"Hyperoxia Causes Mitochondrial Fragmentation in Pulmonary Endothelial Cells by Increasing Expression of Pro-Fission Proteins","volume":"38","author":"Ma","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13054-014-0711-x","article-title":"Arterial hyperoxia and mortality in critically ill patients: A systematic review and meta-analysis","volume":"18","author":"Damiani","year":"2014","journal-title":"Crit. Care"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1097\/CCM.0000000000000998","article-title":"Association Between Arterial Hyperoxia and Outcome in Subsets of Critical Illness","volume":"43","author":"Helmerhorst","year":"2015","journal-title":"Crit. Care Med."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Shenoy, N., Luchtel, R., and Gulani, P. (2020). Considerations for target oxygen saturation in COVID-19 patients: Are we under-shooting?. BMC Med., 18.","DOI":"10.1186\/s12916-020-01735-2"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Ni, Y.-N., Wang, Y.-M., Liang, B.-M., and Liang, Z.-A. (2019). The effect of hyperoxia on mortality in critically ill patients: A systematic review and meta analysis. BMC Pulm. Med., 19.","DOI":"10.1186\/s12890-019-0810-1"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1016\/S0140-6736(18)32201-3","article-title":"Oxygenation targets in acutely ill patients: Still a matter of debate","volume":"392","author":"Rasmussen","year":"2018","journal-title":"Lancet"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1136\/hrt.2008.148742","article-title":"Routine use of oxygen in the treatment of myocardial infarction: Systematic review","volume":"95","author":"Wijesinghe","year":"2008","journal-title":"Heart"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s00101-017-0286-4","article-title":"The WHO recommendation for 80% perioperative oxygen is poorly justified","volume":"66","author":"Volk","year":"2017","journal-title":"Der Anaesthesist"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.bja.2018.11.026","article-title":"Safety of 80% vs 30\u201335% fraction of inspired oxygen in patients undergoing surgery: A systematic review and meta-analysis","volume":"122","author":"Mattishent","year":"2019","journal-title":"Br. J. Anaesth."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1111\/imm.12926","article-title":"Deficient arginase II expression without alteration in arginase I expression attenuated experimental autoimmune encephalomyelitis in mice","volume":"155","author":"Choudry","year":"2018","journal-title":"Immunology"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Gupta, K.K., Donahue, D.L., Sandoval-Cooper, M.J., Castellino, F.J., and Ploplis, V.A. (2015). Abrogation of plasminogen activator inhibitor-1-vitronectin interaction ameliorates acute kidney injury in murine endotoxemia. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0120728"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"e34681","DOI":"10.7554\/eLife.34681","article-title":"HIF-2\u03b1 is essential for carotid body development and function","volume":"7","author":"Macias","year":"2018","journal-title":"Elife"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1101\/gad.1881410","article-title":"Differential activation and antagonistic function of HIF-\u03b1 isoforms in macrophages are essential for NO homeostasis","volume":"24","author":"Takeda","year":"2010","journal-title":"Genes Dev."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. 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