{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:44:04Z","timestamp":1790959444928,"version":"4.1.0"},"reference-count":47,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T00:00:00Z","timestamp":1727395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the German Cardiac Society (DGK)","award":["470814312"],"award-info":[{"award-number":["470814312"]}]},{"name":"the German Cardiac Society (DGK)","award":["MO 1695\/4-1"],"award-info":[{"award-number":["MO 1695\/4-1"]}]},{"name":"the German Cardiac Society (DGK)","award":["91642764"],"award-info":[{"award-number":["91642764"]}]},{"name":"the German Cardiac Society (DGK)","award":["81X2800207"],"award-info":[{"award-number":["81X2800207"]}]},{"DOI":"10.13039\/501100001659","name":"the Deutsche Forschungsgemeinschaft (DFG)","doi-asserted-by":"publisher","award":["470814312"],"award-info":[{"award-number":["470814312"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"the Deutsche Forschungsgemeinschaft (DFG)","doi-asserted-by":"publisher","award":["MO 1695\/4-1"],"award-info":[{"award-number":["MO 1695\/4-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"the Deutsche Forschungsgemeinschaft (DFG)","doi-asserted-by":"publisher","award":["91642764"],"award-info":[{"award-number":["91642764"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"the Deutsche Forschungsgemeinschaft (DFG)","doi-asserted-by":"publisher","award":["81X2800207"],"award-info":[{"award-number":["81X2800207"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Government of Ghana and the Deutscher Akademischer Austauschdienst","award":["470814312"],"award-info":[{"award-number":["470814312"]}]},{"name":"the Government of Ghana and the Deutscher Akademischer Austauschdienst","award":["MO 1695\/4-1"],"award-info":[{"award-number":["MO 1695\/4-1"]}]},{"name":"the Government of Ghana and the Deutscher Akademischer Austauschdienst","award":["91642764"],"award-info":[{"award-number":["91642764"]}]},{"name":"the Government of Ghana and the Deutscher Akademischer Austauschdienst","award":["81X2800207"],"award-info":[{"award-number":["81X2800207"]}]},{"name":"the German Centre for Cardiovascular Research (DZHK)","award":["470814312"],"award-info":[{"award-number":["470814312"]}]},{"name":"the German Centre for Cardiovascular Research (DZHK)","award":["MO 1695\/4-1"],"award-info":[{"award-number":["MO 1695\/4-1"]}]},{"name":"the German Centre for Cardiovascular Research (DZHK)","award":["91642764"],"award-info":[{"award-number":["91642764"]}]},{"name":"the German Centre for Cardiovascular Research (DZHK)","award":["81X2800207"],"award-info":[{"award-number":["81X2800207"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Aim: The primary endothelial NADPH oxidase isoform 4 (NOX4) is notably induced during hypoxia, with emerging evidence suggesting its vasoprotective role through H2O2 production. Therefore, we aimed to elucidate NOX4\u2032s significance in endothelial function under hypoxia. Methods: Human vessels, in addition to murine vessels from Nox4\u2212\/\u2212 mice, were explored. On a functional level, Mulvany myograph experiments were performed. To obtain mechanistical insights, human endothelial cells were cultured under hypoxia with inhibitors of hypoxia-inducible factors. Additionally, endothelial cells were cultured under combined hypoxia and laminar shear stress conditions. Results: In human occluded vessels, NOX4 expression strongly correlated with prostaglandin I2 synthase (PTGIS). Hypoxia significantly elevated NOX4 and PTGIS expression and activity in human endothelial cells. Inhibition of prolyl hydroxylase domain (PHD) enzymes, which stabilize hypoxia-inducible factors (HIFs), increased NOX4 and PTGIS expression even under normoxic conditions. NOX4 mRNA expression was reduced by HIF1a inhibition, while PTGIS mRNA expression was only affected by the inhibition of HIF2a under hypoxia. Endothelial function assessments revealed hypoxia-induced endothelial dysfunction in mesenteric arteries from wild-type mice. Mesenteric arteries from Nox4\u2212\/\u2212 mice exhibited an altered endothelial function under hypoxia, most prominent in the presence of cyclooxygenase inhibitor diclofenac to exclude the impact of prostacyclin. Restored protective laminar shear stress, as it might occur after thrombolysis, angioplasty, or stenting, attenuated the hypoxic response in endothelial cells, reducing HIF1a expression and its target NOX4 while enhancing eNOS expression. Conclusions: Hypoxia strongly induces NOX4 and PTGIS, with a close correlation between both factors in occluded, hypoxic human vessels. This relationship ensured endothelium-dependent vasodilation under hypoxic conditions. Protective laminar blood flow restores eNOS expression and mitigates the hypoxic response on NOX4 and PTGIS.<\/jats:p>","DOI":"10.3390\/antiox13101178","type":"journal-article","created":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T11:19:33Z","timestamp":1727435973000},"page":"1178","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["NADPH Oxidase 4: Crucial for Endothelial Function under Hypoxia\u2014Complementing Prostacyclin"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1214-1807","authenticated-orcid":false,"given":"Heike","family":"Brendel","sequence":"first","affiliation":[{"name":"Division of Vascular Endothelium and Microcirculation, Department of Medicine III, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Mittag","sequence":"additional","affiliation":[{"name":"Division of Vascular Endothelium and Microcirculation, Department of Medicine III, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1490-6474","authenticated-orcid":false,"given":"Anja","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Division of Vascular and Endovascular Surgery, Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helene","family":"Hempel","sequence":"additional","affiliation":[{"name":"Division of Vascular Endothelium and Microcirculation, Department of Medicine III, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sindy","family":"Giebe","sequence":"additional","affiliation":[{"name":"Division of Vascular Endothelium and Microcirculation, Department of Medicine III, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8672-6640","authenticated-orcid":false,"given":"Patrick","family":"Diaba-Nuhoho","sequence":"additional","affiliation":[{"name":"Division of Vascular Endothelium and Microcirculation, Department of Medicine III, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, 01307 Dresden, Germany"},{"name":"Department of Paediatric and Adolescent Medicine, Paediatric Haematology and Oncology, University Hospital M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Wolk","sequence":"additional","affiliation":[{"name":"Division of Vascular and Endovascular Surgery, Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Reeps","sequence":"additional","affiliation":[{"name":"Division of Vascular and Endovascular Surgery, Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9360-9736","authenticated-orcid":false,"given":"Henning","family":"Morawietz","sequence":"additional","affiliation":[{"name":"Division of Vascular Endothelium and Microcirculation, Department of Medicine III, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coy","family":"Brunssen","sequence":"additional","affiliation":[{"name":"Division of Vascular Endothelium and Microcirculation, Department of Medicine III, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ullah, K., and Wu, R. (2021). Hypoxia-Inducible Factor Regulates Endothelial Metabolism in Cardiovascular Disease. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.670653"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.freeradbiomed.2013.05.022","article-title":"Hypoxia: A master regulator of microRNA biogenesis and activity","volume":"64","author":"Nallamshetty","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1124\/mol.113.089623","article-title":"Molecular responses to hypoxia-inducible factor 1alpha and beyond","volume":"85","author":"Brocato","year":"2014","journal-title":"Mol. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.tibs.2012.10.004","article-title":"Emerging novel functions of the oxygen-sensing prolyl hydroxylase domain enzymes","volume":"38","author":"Wong","year":"2013","journal-title":"Trends Biochem. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1242\/jcs.035022","article-title":"HIF at a glance","volume":"122","author":"Pouyssegur","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1182\/blood-2003-07-2240","article-title":"Superoxide dismutase-3 promotes full expression of the EPO response to hypoxia","volume":"104","author":"Suliman","year":"2004","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.neuroscience.2004.12.038","article-title":"Neuronal expression of the NADPH oxidase NOX4, and its regulation in mouse experimental brain ischemia","volume":"132","author":"Vallet","year":"2005","journal-title":"Neuroscience"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1161\/CIRCRESAHA.107.148015","article-title":"Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature","volume":"101","author":"Mittal","year":"2007","journal-title":"Circ. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1089\/ars.2008.2035","article-title":"NOX4 regulates ROS levels under normoxic and hypoxic conditions, triggers proliferation, and inhibits apoptosis in pulmonary artery adventitial fibroblasts","volume":"10","author":"Li","year":"2008","journal-title":"Antioxid. Redox Signal."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sylvester, A.L., Zhang, D.X., Ran, S., and Zinkevich, N.S. (2022). Inhibiting NADPH Oxidases to Target Vascular and Other Pathologies: An Update on Recent Experimental and Clinical Studies. Biomolecules, 12.","DOI":"10.3390\/biom12060823"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1124\/mi.11.1.5","article-title":"NOX isoforms and reactive oxygen species in vascular health","volume":"11","author":"Touyz","year":"2011","journal-title":"Mol. Interv."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1113\/JP283208","article-title":"Ageing and endothelium-mediated vascular dysfunction: The role of the NADPH oxidases","volume":"601","author":"Kwon","year":"2023","journal-title":"J. Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wang, D., Li, J., Luo, G., Zhou, J., Wang, N., Wang, S., Zhao, R., Cao, X., Ma, Y., and Liu, G. (2023). Nox4 as a novel therapeutic target for diabetic vascular complications. Redox Biol., 64.","DOI":"10.1016\/j.redox.2023.102781"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"13304","DOI":"10.1074\/jbc.M110.192138","article-title":"The E-loop is involved in hydrogen peroxide formation by the NADPH oxidase Nox4","volume":"286","author":"Takac","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2710","DOI":"10.1089\/ars.2013.5374","article-title":"Prostacyclin signaling boosts NADPH oxidase 4 in the endothelium promoting cytoprotection and angiogenesis","volume":"20","author":"Peshavariya","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1186\/s12931-023-02559-3","article-title":"Prostaglandin and prostaglandin receptors: Present and future promising therapeutic targets for pulmonary arterial hypertension","volume":"24","author":"Zeng","year":"2023","journal-title":"Respir. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/S1078-5884(03)00385-X","article-title":"Prostacyclin: A vascular mediator","volume":"26","author":"Vane","year":"2003","journal-title":"Eur. J. Vasc. Endovasc. Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/BF00581536","article-title":"The role of prostaglandins in the endothelium-mediated vasodilatory response to hypoxia","volume":"401","author":"Busse","year":"1984","journal-title":"Pflug. Arch."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"18121","DOI":"10.1073\/pnas.1009700107","article-title":"NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis","volume":"107","author":"Zhang","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.atherosclerosissup.2017.05.042","article-title":"Endothelial function and gene expression in perivascular adipose tissue from internal mammary arteries of obese patients with coronary artery disease","volume":"30","author":"Cybularz","year":"2017","journal-title":"Atheroscler. Suppl."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1016\/j.bcp.2010.06.018","article-title":"LW6, a novel HIF-1 inhibitor, promotes proteasomal degradation of HIF-1alpha via upregulation of VHL in a colon cancer cell line","volume":"80","author":"Lee","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/j.molcel.2008.12.004","article-title":"Small-molecule inhibitors of HIF-2a translation link its 5\u2032UTR iron-responsive element to oxygen sensing","volume":"32","author":"Zimmer","year":"2008","journal-title":"Mol. Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1007\/s00395-013-0362-0","article-title":"Impact of Hey2 and COUP-TFII on genes involved in arteriovenous differentiation in primary human arterial and venous endothelial cells","volume":"108","author":"Korten","year":"2013","journal-title":"Basic Res. Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/j.redox.2017.04.008","article-title":"Cigarette smoke extract counteracts atheroprotective effects of high laminar flow on endothelial function","volume":"12","author":"Giebe","year":"2017","journal-title":"Redox Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT-PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Liang, X., Arullampalam, P., Yang, Z., and Ming, X.F. (2019). Hypoxia Enhances Endothelial Intercellular Adhesion Molecule 1 Protein Level Through Upregulation of Arginase Type II and Mitochondrial Oxidative Stress. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.01003"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1161\/CIRCULATIONAHA.111.030775","article-title":"NADPH oxidase 4 promotes endothelial angiogenesis through endothelial nitric oxide synthase activation","volume":"124","author":"Craige","year":"2011","journal-title":"Circulation"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.freeradbiomed.2014.01.027","article-title":"NADPH oxidase 4 promotes cardiac microvascular angiogenesis after hypoxia\/reoxygenation in vitro","volume":"69","author":"Wang","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1242\/jcs.02798","article-title":"Regulation of cardiotrophin-1 expression in mouse embryonic stem cells by HIF-1alpha and intracellular reactive oxygen species","volume":"119","author":"Ateghang","year":"2006","journal-title":"J. Cell Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e00204","DOI":"10.1002\/phy2.204","article-title":"Diet-induced obesity alters skeletal muscle fiber types of male but not female mice","volume":"2","author":"DeNies","year":"2014","journal-title":"Physiol. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1091\/mbc.e09-12-1003","article-title":"The NADPH oxidase subunit NOX4 is a new target gene of the hypoxia-inducible factor-1","volume":"21","author":"Diebold","year":"2010","journal-title":"Mol. Biol. Cell"},{"key":"ref_32","first-page":"7929","article-title":"Primary endothelial cell-specific 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. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1194\/jlr.M011007","article-title":"Hypoxia upregulates PGI-synthase and increases PGI2 release in human vascular cells exposed to inflammatory stimuli","volume":"52","author":"Camacho","year":"2011","journal-title":"J. Lipid Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1182\/blood-2004-07-2958","article-title":"Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1","volume":"105","author":"Manalo","year":"2005","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"110209","DOI":"10.1016\/j.cellsig.2021.110209","article-title":"Functional and HRE motifs count analysis of induction of selected hypoxia-responsive genes by HIF-1 and HIF-2 in human umbilical endothelial cells","volume":"90","author":"Cabaj","year":"2022","journal-title":"Cell. Signal."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.cardiores.2003.12.008","article-title":"p21(Waf1\/Cip1\/Sdi1) mediates shear stress-dependent antiapoptotic function","volume":"61","author":"Mattiussi","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1165\/rcmb.2022-0340OC","article-title":"Shear Stress Markedly Alters the Proteomic Response to Hypoxia in Human Pulmonary Endothelial Cells","volume":"68","author":"Kostyunina","year":"2023","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1086\/687756","article-title":"NADPH oxidase 4 is not involved in hypoxia-induced pulmonary hypertension","volume":"6","author":"Veith","year":"2016","journal-title":"Pulm. Circ."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1165\/rcmb.2008-0132OC","article-title":"Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model","volume":"42","author":"Nisbet","year":"2010","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7368","DOI":"10.1073\/pnas.95.13.7368","article-title":"Inhibition of hypoxia-inducible factor 1 activity by nitric oxide donors in hypoxia","volume":"95","author":"Sogawa","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/S0006-291X(02)00729-5","article-title":"HIF-1alpha-prolyl hydroxylase: Molecular target of nitric oxide in the hypoxic signal transduction pathway","volume":"295","author":"Wang","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"9038","DOI":"10.1074\/jbc.274.13.9038","article-title":"Inhibition of hypoxia-inducible factor 1 activation by carbon monoxide and nitric oxide. Implications for oxygen sensing and signaling","volume":"274","author":"Huang","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1126\/science.1088805","article-title":"Redistribution of intracellular oxygen in hypoxia by nitric oxide: Effect on HIF1alpha","volume":"302","author":"Hagen","year":"2003","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Cattaneo, M.G., Cappellini, E., Benfante, R., Ragni, M., Omodeo-Sale, F., Nisoli, E., Borgese, N., and Vicentini, L.M. (2011). Chronic deficiency of nitric oxide affects hypoxia inducible factor-1alpha (HIF-1alpha) stability and migration in human endothelial cells. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0029680"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1161\/01.RES.86.3.347","article-title":"Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide","volume":"86","author":"Drummond","year":"2000","journal-title":"Circ. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1038\/21224","article-title":"Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation","volume":"399","author":"Dimmeler","year":"1999","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1097\/HJH.0000000000003478","article-title":"Vasoprotective effects of NOX4 are mediated via polymerase and transient receptor potential melastatin 2 cation channels in endothelial cells","volume":"41","author":"Lacchini","year":"2023","journal-title":"J. Hypertens."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/13\/10\/1178\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:05:29Z","timestamp":1760112329000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/13\/10\/1178"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,27]]},"references-count":47,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["antiox13101178"],"URL":"https:\/\/doi.org\/10.3390\/antiox13101178","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,27]]}}}