{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:01:52Z","timestamp":1791388912063,"version":"4.3.3"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T00:00:00Z","timestamp":1635120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R56HL127079"],"award-info":[{"award-number":["R56HL127079"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,4,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The mechanism and markers of cardiovascular disease (CVD) in obstructive sleep apnea (OSA) remain unknown. The microcirculation is the site of early changes in OSA patients who are free of CVD risk.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Patients with newly diagnosed moderate to severe OSA (n = 7) were studied before and 12 weeks after intensive treatment with continuous positive airway pressure (CPAP), along with weight and age matched controls (n = 7). Microcirculatory vessels were isolated from gluteal biopsies and changes in critical functional genes were measured.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The following genes changed after 12 weeks of intensive CPAP therapy in the microcirculatory vessels: angiotensin receptor type 1 (AGTR-1) (11.6 (3.4) to 6 (0.8); P = 0.019); NADPH oxidase (NOX4) (0.85 (0.02) to 0.79 (0.11); P = 0.016); and dimethylarginine dimethylaminohydrolase (DDAH 1) (1 (0.31) to 0.55 (0.1); P = 0.028). Despite decreased nitric oxide (NO) availability as measured indirectly through brachial artery flow-mediated dilation, endothelial NO synthase (NOS3) did not change with CPAP. Other disease markers of OSA that changed with treatment in the microcirculation were endothelin, hypoxia inducible factor 1a, nuclear factor kappa B, interleukin-8, and interleukin-6.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>In this ex vivo evaluation of the microcirculation of patients with OSA and no CVD risk, several pathways of CVD were activated supporting that OSA independently induces microcirculatory endothelial dysfunction and serving as disease-specific markers for future pharmacological targeting of OSA-related CVD risk. The findings support the role of renin\u2013angiotensin activation and endothelial oxidative stress in the decreased microcirculatory NO availability in OSA.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ajh\/hpab169","type":"journal-article","created":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T03:11:52Z","timestamp":1634785912000},"page":"347-355","source":"Crossref","is-referenced-by-count":13,"title":["Pathways of Microcirculatory Endothelial Dysfunction in Obstructive Sleep Apnea: A Comprehensive <i>Ex Vivo<\/i> Evaluation in Human Tissue"],"prefix":"10.1093","volume":"35","author":[{"given":"Mikhail A","family":"Gavrilin","sequence":"first","affiliation":[{"name":"The Sleep Heart Program, The Ohio State University , Columbus, Ohio , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Porter","sequence":"additional","affiliation":[{"name":"The Center for Biostatistics, The Ohio State University , Columbus, Ohio , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Samouilov","sequence":"additional","affiliation":[{"name":"Department of Medicine, The Division of Cardiovascular Medicine, The Ohio State University , Columbus, Ohio , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4240-5754","authenticated-orcid":false,"given":"Rami N","family":"Khayat","sequence":"additional","affiliation":[{"name":"The Sleep Heart Program, The Ohio State University , Columbus, Ohio , USA"},{"name":"The Division of Pulmonary and Critical Medicine and the UCI Sleep Disorders Center, Departments of Medicine and Psychiatry, the University of California-Irvine , Irvine, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,10,25]]},"reference":[{"key":"2022100713223834400_CIT0001","doi-asserted-by":"crossref","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":"2022100713223834400_CIT0002","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1001\/jama.283.14.1829","article-title":"Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study","volume":"283","author":"Nieto","year":"2000","journal-title":"JAMA"},{"key":"2022100713223834400_CIT0003","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1172\/JCI119120","article-title":"Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model","volume":"99","author":"Brooks","year":"1997","journal-title":"J Clin Invest"},{"key":"2022100713223834400_CIT0004","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.1001\/jama.2013.281250","article-title":"Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial","volume":"310","author":"Mart\u00ednez-Garc\u00eda","year":"2013","journal-title":"JAMA"},{"key":"2022100713223834400_CIT0005","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1164\/rccm.200703-500OC","article-title":"Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea","volume":"176","author":"Drager","year":"2007","journal-title":"Am J Respir Crit Care Med"},{"key":"2022100713223834400_CIT0006","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1164\/ajrccm.162.1.9905035","article-title":"Respiratory disturbance index: an independent predictor of mortality in coronary artery disease","volume":"162","author":"Peker","year":"2000","journal-title":"Am J Respir Crit Care Med"},{"key":"2022100713223834400_CIT0007","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1164\/rccm.200505-702OC","article-title":"Association of sleep-disordered breathing and the occurrence of stroke","volume":"172","author":"Arzt","year":"2005","journal-title":"Am J Respir Crit Care Med"},{"key":"2022100713223834400_CIT0008","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1161\/01.STR.0000208215.49243.c3","article-title":"Sleep-disordered breathing and acute ischemic stroke: diagnosis, risk factors, treatment, evolution, and long-term clinical outcome","volume":"37","author":"Bassetti","year":"2006","journal-title":"Stroke"},{"key":"2022100713223834400_CIT0009","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1164\/ajrccm.153.6.8665046","article-title":"The association of sudden unexpected infant death with obstructive sleep apnea","volume":"153","author":"Tishler","year":"1996","journal-title":"Am J Respir Crit Care Med"},{"key":"2022100713223834400_CIT0010","doi-asserted-by":"crossref","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":"2022100713223834400_CIT0011","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1097\/HJH.0000000000000372","article-title":"Effects of continuous positive airway pressure on blood pressure in patients with resistant hypertension and obstructive sleep apnea: a meta-analysis","volume":"32","author":"Iftikhar","year":"2014","journal-title":"J Hypertens"},{"key":"2022100713223834400_CIT0012","doi-asserted-by":"crossref","first-page":"2276","DOI":"10.1056\/NEJMoa1306766","article-title":"CPAP versus oxygen in obstructive sleep apnea","volume":"370","author":"Gottlieb","year":"2014","journal-title":"N Engl J Med"},{"key":"2022100713223834400_CIT0013","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1183\/09031936.00047709","article-title":"A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea","volume":"35","author":"Lam","year":"2010","journal-title":"Eur Respir J"},{"key":"2022100713223834400_CIT0014","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1056\/NEJMoa1606599","article-title":"CPAP for prevention of cardiovascular events in obstructive sleep apnea","volume":"375","author":"McEvoy","year":"2016","journal-title":"N Engl J Med"},{"key":"2022100713223834400_CIT0015","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1164\/rccm.201601-0088OC","article-title":"Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with nonsleepy obstructive sleep apnea. The RICCADSA randomized controlled trial","volume":"194","author":"Peker","year":"2016","journal-title":"Am J Respir Crit Care Med"},{"key":"2022100713223834400_CIT0016","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1056\/NEJMoa1506459","article-title":"Adaptive servo-ventilation for central sleep apnea in systolic heart failure","volume":"373","author":"Cowie","year":"2015","journal-title":"N Engl J Med"},{"key":"2022100713223834400_CIT0017","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1001\/jama.2016.20325","article-title":"Screening for obstructive sleep apnea in adults: US Preventive Services Task Force recommendation statement","volume":"317","author":"Bibbins-Domingo","year":"2017","journal-title":"JAMA"},{"key":"2022100713223834400_CIT0018","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1001\/jama.2017.7967","article-title":"Association of positive airway pressure with cardiovascular events and death in adults with sleep apnea: a systematic review and meta-analysis","volume":"318","author":"Yu","year":"2017","journal-title":"JAMA"},{"key":"2022100713223834400_CIT0019","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1161\/01.CIR.81.6.1762","article-title":"Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo. Blunted response in essential hypertension","volume":"81","author":"Linder","year":"1990","journal-title":"Circulation"},{"key":"2022100713223834400_CIT0020","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1097\/00005344-199703000-00015","article-title":"Cutaneous vasodilation to acetylcholine in patients with essential hypertension","volume":"29","author":"Rossi","year":"1997","journal-title":"J Cardiovasc Pharmacol"},{"key":"2022100713223834400_CIT0021","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.resp.2014.12.012","article-title":"Endothelial nitric oxide synthase uncoupling: a novel pathway in OSA induced vascular endothelial dysfunction","volume":"207","author":"Varadharaj","year":"2015","journal-title":"Respir Physiol Neurobiol"},{"key":"2022100713223834400_CIT0022","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1164\/rccm.201002-0162OC","article-title":"Endothelial dysfunction in the microcirculation of patients with obstructive sleep apnea","volume":"182","author":"Patt","year":"2010","journal-title":"Am J Respir Crit Care Med"},{"key":"2022100713223834400_CIT0023","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1093\/ajh\/hpx174","article-title":"Angiotensin receptor expression and vascular endothelial dysfunction in obstructive sleep apnea","volume":"31","author":"Khayat","year":"2018","journal-title":"Am J Hypertens"},{"key":"2022100713223834400_CIT0024","doi-asserted-by":"crossref","DOI":"10.1093\/sleep\/zsaa286","article-title":"Complement promotes endothelial von Willebrand factor and angiopoietin-2 release in obstructive sleep apnea","volume":"44","author":"Gao","year":"2021","journal-title":"Sleep"},{"key":"2022100713223834400_CIT0025","doi-asserted-by":"crossref","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":"2022100713223834400_CIT0026","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1161\/01.CIR.97.18.1837","article-title":"Prediction of coronary heart disease using risk factor categories","volume":"97","author":"Wilson","year":"1998","journal-title":"Circulation"},{"key":"2022100713223834400_CIT0027","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1161\/CIRCULATIONAHA.107.699579","article-title":"General cardiovascular risk profile for use in primary care: the Framingham Heart Study","volume":"117","author":"D\u2019Agostino","year":"2008","journal-title":"Circulation"},{"key":"2022100713223834400_CIT0028","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1093\/ajh\/hpx174","article-title":"Angiotensin receptor expression and vascular endothelial dysfunction in obstructive sleep apnea","volume":"31","author":"Khayat","year":"2018","journal-title":"Am J Hypertens"},{"key":"2022100713223834400_CIT0029","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/S0735-1097(01)01746-6","article-title":"Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force","volume":"39","author":"Corretti","year":"2002","journal-title":"J Am Coll Cardiol"},{"key":"2022100713223834400_CIT0030","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1073\/pnas.0504271103","article-title":"Internalization and phagosome escape required for Francisella to induce human monocyte IL-1beta processing and release","volume":"103","author":"Gavrilin","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022100713223834400_CIT0031","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1164\/rccm.200703-418OC","article-title":"Inflammasome mRNA expression in human monocytes during early septic shock","volume":"177","author":"Fahy","year":"2008","journal-title":"Am J Respir Crit Care Med"},{"key":"2022100713223834400_CIT0032","doi-asserted-by":"crossref","first-page":"e70559","DOI":"10.1371\/journal.pone.0070559","article-title":"Molecular biomarkers of vascular dysfunction in obstructive sleep apnea","volume":"8","author":"Kaczmarek","year":"2013","journal-title":"PLoS One"},{"key":"2022100713223834400_CIT0033","doi-asserted-by":"crossref","first-page":"27038","DOI":"10.1074\/jbc.M802269200","article-title":"Phosphorylation of endothelial nitric-oxide synthase regulates superoxide generation from the enzyme","volume":"283","author":"Chen","year":"2008","journal-title":"J Biol Chem"},{"key":"2022100713223834400_CIT0034","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1161\/01.CIR.0000015853.59427.32","article-title":"Paradoxical reduction of fatty streak formation in mice lacking endothelial nitric oxide synthase","volume":"105","author":"Shi","year":"2002","journal-title":"Circulation"},{"key":"2022100713223834400_CIT0035","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1172\/JCI0215215","article-title":"Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice","volume":"110","author":"Ozaki","year":"2002","journal-title":"J Clin Invest"},{"issue":"Pt 1","key":"2022100713223834400_CIT0036","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1042\/bj3230159","article-title":"Characterization of bovine endothelial nitric oxide synthase as a homodimer with down-regulated uncoupled NADPH oxidase activity: tetrahydrobiopterin binding kinetics and role of haem in dimerization","volume":"323","author":"List","year":"1997","journal-title":"Biochem J"},{"key":"2022100713223834400_CIT0037","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1161\/01.CIR.0000012748.58444.08","article-title":"Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase","volume":"105","author":"Guzik","year":"2002","journal-title":"Circulation"},{"key":"2022100713223834400_CIT0038","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1038\/nature09599","article-title":"S-glutathionylation uncouples eNOS and regulates its cellular and vascular function","volume":"468","author":"Chen","year":"2010","journal-title":"Nature"},{"key":"2022100713223834400_CIT0039","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1161\/hh0901.090299","article-title":"Novel gp91(phox) homologues in vascular smooth muscle cells: nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways","volume":"88","author":"Lass\u00e8gue","year":"2001","journal-title":"Circ Res"},{"key":"2022100713223834400_CIT0040","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1172\/JCI118623","article-title":"Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH\/NADPH oxidase activation. Contribution to alterations of vasomotor tone","volume":"97","author":"Rajagopalan","year":"1996","journal-title":"J Clin Invest"},{"key":"2022100713223834400_CIT0041","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.resp.2012.05.025","article-title":"Effect of AT1 receptor blockade on intermittent hypoxia-induced endothelial dysfunction","volume":"183","author":"Marcus","year":"2012","journal-title":"Respir Physiol Neurobiol"},{"key":"2022100713223834400_CIT0042","doi-asserted-by":"crossref","first-page":"5529","DOI":"10.1113\/jphysiol.2011.218156","article-title":"Losartan abolishes oxidative stress induced by intermittent hypoxia in humans","volume":"589","author":"Pialoux","year":"2011","journal-title":"J Physiol"},{"key":"2022100713223834400_CIT0043","first-page":"4164","article-title":"The impact of obstructive sleep apnea syndrome on renin and aldosterone","volume":"19","author":"Lykouras","year":"2015","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"2022100713223834400_CIT0044","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1164\/rccm.201502-0383OC","article-title":"Nocturnal hypoxemia severity and renin-angiotensin system activity in obstructive sleep apnea","volume":"192","author":"Zalucky","year":"2015","journal-title":"Am J Respir Crit Care Med"},{"key":"2022100713223834400_CIT0045","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1164\/rccm.201403-0526OC","article-title":"Evaluation of continuous positive airway pressure therapy on renin-angiotensin system activity in obstructive sleep apnea","volume":"190","author":"Nicholl","year":"2014","journal-title":"Am J Respir Crit Care Med"},{"key":"2022100713223834400_CIT0046","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1067\/mai.2001.112270","article-title":"Soluble TNF-alpha receptor 1 and IL-6 plasma levels in humans subjected to the sleep deprivation model of spaceflight","volume":"107","author":"Shearer","year":"2001","journal-title":"J Allergy Clin Immunol"}],"container-title":["American Journal of Hypertension"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajh\/advance-article-pdf\/doi\/10.1093\/ajh\/hpab169\/41325810\/hpab169.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajh\/article-pdf\/35\/4\/347\/46374269\/hpab169.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajh\/article-pdf\/35\/4\/347\/46374269\/hpab169.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,7]],"date-time":"2022-10-07T14:21:17Z","timestamp":1665152477000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajh\/article\/35\/4\/347\/6409957"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,25]]},"references-count":46,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,10,25]]},"published-print":{"date-parts":[[2022,4,2]]}},"URL":"https:\/\/doi.org\/10.1093\/ajh\/hpab169","relation":{},"ISSN":["0895-7061","1941-7225"],"issn-type":[{"value":"0895-7061","type":"print"},{"value":"1941-7225","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,4,1]]},"published":{"date-parts":[[2021,10,25]]}}}