{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:05:36Z","timestamp":1790190336181,"version":"4.1.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,12]],"date-time":"2021-07-12T00:00:00Z","timestamp":1626048000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-16-1-0711"],"award-info":[{"award-number":["W81XWH-16-1-0711"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>\n                    Obstructive sleep apnea (OSA) is a common breathing disorder affecting a significant percentage of the adult population. OSA is an independent risk factor for cardiovascular disease (CVD); however, the underlying mechanisms are not completely understood. Since the severity of hypoxia correlates with some of the cardiovascular effects, intermittent hypoxia (IH) is thought to be one of the mechanisms by which OSA may cause CVD. Here, we investigated the effect of IH on endothelial cell (EC) activation, characterized by the expression of inflammatory genes, that is known to play an important role in the pathogenesis of CVD. Exposure of C57BL\/6 mice to IH led to aortic EC activation, while\n                    <jats:italic>in vitro<\/jats:italic>\n                    exposure of ECs to IH failed to do so, suggesting that IH does not induce EC activation directly, but indirectly. One of the consequences of IH is activation of the sympathetic nervous system and catecholamine release. We found that exposure of mice to IH caused elevation of circulating levels of catecholamines. Inhibition of the IH-induced increase in catecholamines by pharmacologic inhibition or by adrenalectomy or carotid body ablation prevented the IH-induced EC activation in mice. Supporting a key role for catecholamines, epinephrine alone was sufficient to cause EC activation\n                    <jats:italic>in vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Together, these results suggested that IH does not directly induce EC activation, but does so indirectly\n                    <jats:italic>via<\/jats:italic>\n                    release of catecholamines. These results suggest that targeting IH-induced sympathetic nerve activity and catecholamine release may be a potential therapeutic target to attenuate the CV effects of OSA.\n                  <\/jats:p>","DOI":"10.3389\/fphys.2021.701995","type":"journal-article","created":{"date-parts":[[2021,7,12]],"date-time":"2021-07-12T02:14:55Z","timestamp":1626056095000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Intermittent Hypoxia-Induced Activation of Endothelial Cells Is Mediated via Sympathetic Activation-Dependent Catecholamine Release"],"prefix":"10.3389","volume":"12","author":[{"given":"Rengul","family":"Cetin-Atalay","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo Y.","family":"Meliton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parker S.","family":"Woods","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitlyn A.","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Jie","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayasri","family":"Nanduri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert B.","family":"Hamanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanduri","family":"Prabhakar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f6khan M.","family":"Mutlu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,12]]},"reference":[{"key":"ref1","year":"2014"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.sleh.2017.10.006","article-title":"Prevalence and comorbidity of sleep conditions in Australian adults: 2016 sleep Health Foundation national survey","volume":"4","author":"Appleton","year":"2018","journal-title":"Sleep Health"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1164\/rccm.201012-2033OC","article-title":"The inflammatory preatherosclerotic remodeling induced by intermittent hypoxia is attenuated by RANTES\/CCL5 inhibition","volume":"184","author":"Arnaud","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/S2213-2600(19)30198-5","article-title":"Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis","volume":"7","author":"Benjafield","year":"2019","journal-title":"Lancet Respir. Med."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"243","DOI":"10.3978\/j.issn.2072-1439.2015.11.14","article-title":"The sympathetic nervous system and catecholamines metabolism in obstructive sleep apnoea","volume":"8","author":"Bisogni","year":"2016","journal-title":"J. Thorac. Dis."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1763","DOI":"10.1378\/chest.103.6.1763","article-title":"Augmented resting sympathetic activity in awake patients with obstructive sleep apnea","volume":"103","author":"Carlson","year":"1993","journal-title":"Chest"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"2935","DOI":"10.1172\/JCI75157","article-title":"Beta(2)-adrenergic agonists augment air pollution-induced IL-6 release and thrombosis","volume":"124","author":"Chiarella","year":"2014","journal-title":"J. Clin. Invest."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1161\/CIRCULATIONAHA.106.652859","article-title":"Endothelial function and dysfunction: testing and clinical relevance","volume":"115","author":"Deanfield","year":"2007","journal-title":"Circulation"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1152\/physrev.00043.2008","article-title":"Pathophysiology of sleep apnea","volume":"90","author":"Dempsey","year":"2010","journal-title":"Physiol. Rev."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1164\/ajrccm.165.7.2104126","article-title":"Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients","volume":"165","author":"Dyugovskaya","year":"2002","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1183\/09031936.02.00106402","article-title":"Obstructive sleep apnoea and urine catecholamines in hypertensive males: a population-based study","volume":"19","author":"Elmasry","year":"2002","journal-title":"Eur. Respir. J."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"165","DOI":"10.3389\/fcvm.2019.00165","article-title":"Single cell analysis of endothelial cells identified organ-specific molecular signatures and heart-specific cell populations and molecular features","volume":"6","author":"Feng","year":"2019","journal-title":"Front. Cardiovasc. Med."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1600","DOI":"10.1152\/jappl.2001.90.4.1600","article-title":"Invited review: physiological consequences of intermittent hypoxia: systemic blood pressure","volume":"90","author":"Fletcher","year":"2001","journal-title":"J. Appl. Physiol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1093\/sleep\/10.1.35","article-title":"Urinary catecholamines before and after tracheostomy in patients with obstructive sleep apnea and hypertension","volume":"10","author":"Fletcher","year":"1987","journal-title":"Sleep"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"3287","DOI":"10.1113\/jphysiol.2009.171553","article-title":"Cardiovascular and cerebrovascular responses to acute hypoxia following exposure to intermittent hypoxia in healthy humans","volume":"587","author":"Foster","year":"2009","journal-title":"J. Physiol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"635","DOI":"10.3389\/fneur.2018.00635","article-title":"Obstructive sleep apnea: From intermittent hypoxia to cardiovascular complications via blood platelets","volume":"9","author":"Gabryelska","year":"2018","journal-title":"Front. Neurol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1152\/physrev.00004.2012","article-title":"Molecular biology of atherosclerosis","volume":"93","author":"Hopkins","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"590377","DOI":"10.3389\/fgene.2021.590377","article-title":"Single-cell transcriptional profiling reveals sex and age diversity of gene expression in mouse endothelial cells","volume":"12","author":"Huang","year":"2021","journal-title":"Front. Genet."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.1136\/bmj.316.7141.1328","article-title":"Endothelial cell activation. A central pathophysiological process","volume":"316","author":"Hunt","year":"1998","journal-title":"BMJ"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"2270","DOI":"10.1161\/CIRCULATIONAHA.107.741512","article-title":"Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea","volume":"117","author":"Jelic","year":"2008","journal-title":"Circulation"},{"key":"ref21","first-page":"199","article-title":"Pharmacological actions of 6-hydroxydopamine","volume":"26","author":"Kostrzewa","year":"1974","journal-title":"Pharmacol. Rev."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/978-3-319-18440-1_21","article-title":"Carotid body Chemoreflex mediates intermittent hypoxia-induced oxidative stress in the adrenal medulla","volume":"860","author":"Kumar","year":"2015","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1113\/jphysiol.2006.112524","article-title":"Chronic intermittent hypoxia induces hypoxia-evoked catecholamine efflux in adult rat adrenal medulla via oxidative stress","volume":"575","author":"Kumar","year":"2006","journal-title":"J. Physiol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1593","DOI":"10.1097\/00004872-199715120-00060","article-title":"Hypertension caused by chronic intermittent hypoxia--influence of chemoreceptors and sympathetic nervous system","volume":"15","author":"Lesske","year":"1997","journal-title":"J. Hypertens."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1016\/S0140-6736(05)71141-7","article-title":"Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study","volume":"365","author":"Marin","year":"2005","journal-title":"Lancet"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1378\/chest.103.3.722","article-title":"Catecholamines and blood pressure in obstructive sleep apnea syndrome","volume":"103","author":"Marrone","year":"1993","journal-title":"Chest"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.5665\/sleep\/31.8.1079","article-title":"Sleep apnea as an independent risk factor for all-cause mortality: The Busselton Health Study","volume":"31","author":"Marshall","year":"2008","journal-title":"Sleep"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1183\/09031936.00027406","article-title":"Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities","volume":"29","author":"McNicholas","year":"2007","journal-title":"Eur. Respir. J."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.5664\/jcsm.3070","article-title":"Serum inflammatory markers in obstructive sleep apnea: a meta-analysis","volume":"9","author":"Nadeem","year":"2013","journal-title":"J. Clin. Sleep Med."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"3087","DOI":"10.1113\/JP274833","article-title":"DNA methylation in the central and efferent limbs of the chemoreflex requires carotid body neural activity","volume":"596","author":"Nanduri","year":"2018","journal-title":"J. Physiol."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1593","DOI":"10.1152\/jappl.2001.90.4.1593","article-title":"Invited review: Physiological and pathophysiological responses to intermittent hypoxia","volume":"90","author":"Neubauer","year":"2001","journal-title":"J. Appl. Physiol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"2342","DOI":"10.1152\/japplphysiol.00613.2002","article-title":"Reactive oxygen species in the plasticity of respiratory behavior elicited by chronic intermittent hypoxia","volume":"94","author":"Peng","year":"2003","journal-title":"J. Appl. Physiol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1152\/japplphysiol.00820.2003","article-title":"Effect of two paradigms of chronic intermittent hypoxia on carotid body sensory activity","volume":"96","author":"Peng","year":"2004","journal-title":"J. Appl. Physiol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"2054","DOI":"10.1152\/jn.00067.2021","article-title":"Role of olfactory receptor78 in carotid body-dependent sympathetic activation and hypertension in murine models of chronic intermittent hypoxia","volume":"125","author":"Peng","year":"2021","journal-title":"J. Neurophysiol."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"3841","DOI":"10.1113\/jphysiol.2014.273789","article-title":"Regulation of hypoxia-inducible factor-alpha isoforms and redox state by carotid body neural activity in rats","volume":"592","author":"Peng","year":"2014","journal-title":"J. Physiol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1113\/jphysiol.2006.114033","article-title":"Heterozygous HIF-1alpha deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia","volume":"577","author":"Peng","year":"2006","journal-title":"J. Physiol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1113\/EP085624","article-title":"Carotid body chemoreflex: a driver of autonomic abnormalities in sleep apnoea","volume":"101","author":"Prabhakar","year":"2016","journal-title":"Exp. Physiol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1513\/pats.200709-155MG","article-title":"The epidemiology of adult obstructive sleep apnea","volume":"5","author":"Punjabi","year":"2008","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/1471-2466-12-60","article-title":"Obstructive sleep apnea and multimorbidity","volume":"12","author":"Robichaud-Halle","year":"2012","journal-title":"BMC Pulm. Med."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"e10","DOI":"10.1017\/gheg.2018.9","article-title":"Association between multimorbidity and undiagnosed obstructive sleep apnea severity and their impact on quality of life in men over 40 years old","volume":"3","author":"Ruel","year":"2018","journal-title":"Glob. Health. Epidemiol. Genom."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1897","DOI":"10.1172\/JCI118235","article-title":"Sympathetic neural mechanisms in obstructive sleep apnea","volume":"96","author":"Somers","year":"1995","journal-title":"J. Clin. Invest."},{"key":"ref42","first-page":"213","article-title":"Adrenergic mechanism in the control of endothelial function","volume":"1","author":"Sorriento","year":"2011","journal-title":"Transl. Med. UniSa."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"e54877","DOI":"10.7554\/eLife.54877","article-title":"Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response","volume":"9","author":"Sun","year":"2020","journal-title":"eLife"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"e0192671","DOI":"10.1371\/journal.pone.0192671","article-title":"Prevalence of several somatic diseases depends on the presence and severity of obstructive sleep apnea","volume":"13","author":"Tveit","year":"2018","journal-title":"PLoS One"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"e25217","DOI":"10.7554\/eLife.25217","article-title":"HIF-1alpha is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium","volume":"6","author":"Wu","year":"2017","journal-title":"eLife"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1016\/j.sleep.2013.07.006","article-title":"Effects of continuous positive airway pressure therapy on systemic inflammation in obstructive sleep apnea: A meta-analysis","volume":"14","author":"Xie","year":"2013","journal-title":"Sleep Med."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"2034","DOI":"10.1056\/NEJMoa043104","article-title":"Obstructive sleep apnea as a risk factor for stroke and death","volume":"353","author":"Yaggi","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref48","first-page":"246","article-title":"Burden of sleep apnea: Rationale, design, and major findings of the Wisconsin Sleep Cohort study","volume":"108","author":"Young","year":"2009","journal-title":"WMJ"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"1230","DOI":"10.1056\/NEJM199304293281704","article-title":"The occurrence of sleep-disordered breathing among middle-aged adults","volume":"328","author":"Young","year":"1993","journal-title":"N. Engl. J. Med."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"4321","DOI":"10.1074\/jbc.M407706200","article-title":"Ca2+\/calmodulin kinase-dependent activation of hypoxia inducible factor 1 transcriptional activity in cells subjected to intermittent hypoxia","volume":"280","author":"Yuan","year":"2005","journal-title":"J. Biol. Chem."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.701995\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,12]],"date-time":"2021-07-12T02:15:02Z","timestamp":1626056102000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.701995\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,12]]},"references-count":50,"alternative-id":["10.3389\/fphys.2021.701995"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2021.701995","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,12]]},"article-number":"701995"}}