{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T12:50:14Z","timestamp":1793278214963,"version":"4.5.0"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,9,20]],"date-time":"2018-09-20T00:00:00Z","timestamp":1537401600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,9,20]],"date-time":"2018-09-20T00:00:00Z","timestamp":1537401600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"U.S. Department of Health &amp; Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["HL65176"],"award-info":[{"award-number":["HL65176"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health &amp; Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["HL65176"],"award-info":[{"award-number":["HL65176"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["17GRNT33660138"],"award-info":[{"award-number":["17GRNT33660138"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Vascular dysfunction and insulin resistance (IR) are associated with obstructive sleep apnea (OSA), which is characterized by frequent episodes of nocturnal intermittent hypoxia (IH). While it is recognized that the balance between vasoconstrictive (endothelin-1) and vasodilatory molecules (nitric oxide, NO) determine vascular profile, molecular mechanisms contributing to vascular dysfunction and IR in OSA are not completely understood. Caveolin-1 is a membrane protein which regulates endothelial nitric oxide synthase (eNOS) activity which is responsible for NO generation and cellular insulin-signaling. Hence, we examined the effects of IH on caveolin-1, eNOS, and endothelin-1 in human coronary artery endothelial cells in the context of IR. Chronic 3-day IH exposure up-regulated caveolin-1 and endothelin-1 expression while reducing NO. Also, IH altered insulin-mediated activation of AKT but not ERK resulting in increased endothelin-1 transcription. Similarly, caveolin-1 overexpression attenuated basal and insulin-stimulated NO synthesis along with impaired insulin-dependent activation of AKT and eNOS, with no effect on insulin-stimulated ERK1\/2 phosphorylation and endothelin-1 transcription. Our data suggest that IH contributes to a vasoconstrictive profile and to pathway-selective vascular IR, whereby insulin potentiates ET-1 expression. Moreover, IH may partly mediate its effects on NO and insulin-signaling via upregulating caveolin-1 expression.<\/jats:p>","DOI":"10.1038\/s41598-018-32490-3","type":"journal-article","created":{"date-parts":[[2018,9,14]],"date-time":"2018-09-14T10:54:33Z","timestamp":1536922473000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Intermittent hypoxia regulates vasoactive molecules and alters insulin-signaling in vascular endothelial cells"],"prefix":"10.1038","volume":"8","author":[{"given":"Pragya","family":"Sharma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virend K.","family":"Somers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy E.","family":"Peterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuebo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangxi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prachi","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,9,20]]},"reference":[{"key":"32490_CR1","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1016\/j.jacc.2008.05.002","volume":"52","author":"VK Somers","year":"2008","unstructured":"Somers, V. K. et al. Sleep apnea and cardiovascular disease: an American Heart Association\/American College of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. J Am Coll Cardiol 52, 686\u2013717, https:\/\/doi.org\/10.1016\/j.jacc.2008.05.002 (2008).","journal-title":"J Am Coll Cardiol"},{"key":"32490_CR2","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.2147\/VHRM.S4078","volume":"4","author":"A Atkeson","year":"2008","unstructured":"Atkeson, A. & Jelic, S. Mechanisms of endothelial dysfunction in obstructive sleep apnea. Vasc Health Risk Manag 4, 1327\u20131335 (2008).","journal-title":"Vasc Health Risk Manag"},{"key":"32490_CR3","doi-asserted-by":"publisher","first-page":"40091","DOI":"10.1074\/jbc.M205948200","volume":"277","author":"W Schubert","year":"2002","unstructured":"Schubert, W. et al. Microvascular hyperpermeability in caveolin-1 (\u2212\/\u2212) knock-out mice. Treatment with a specific nitric-oxide synthase inhibitor, L-NAME, restores normal microvascular permeability in Cav-1 null mice. The Journal of biological chemistry 277, 40091\u201340098, https:\/\/doi.org\/10.1074\/jbc.M205948200 (2002).","journal-title":"The Journal of biological chemistry"},{"key":"32490_CR4","doi-asserted-by":"publisher","first-page":"2166","DOI":"10.1164\/ajrccm.162.6.2002126","volume":"162","author":"MS Ip","year":"2000","unstructured":"Ip, M. S. et al. Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure. Am J Respir Crit Care Med 162, 2166\u20132171, https:\/\/doi.org\/10.1164\/ajrccm.162.6.2002126 (2000).","journal-title":"Am J Respir Crit Care Med"},{"key":"32490_CR5","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/332411a0","volume":"332","author":"M Yanagisawa","year":"1988","unstructured":"Yanagisawa, M. et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332, 411\u2013415, https:\/\/doi.org\/10.1038\/332411a0 (1988).","journal-title":"Nature"},{"key":"32490_CR6","doi-asserted-by":"publisher","first-page":"18522","DOI":"10.1074\/jbc.272.30.18522","volume":"272","author":"H Ju","year":"1997","unstructured":"Ju, H., Zou, R., Venema, V. J. & Venema, R. C. Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity. The Journal of biological chemistry 272, 18522\u201318525 (1997).","journal-title":"The Journal of biological chemistry"},{"key":"32490_CR7","doi-asserted-by":"publisher","first-page":"2013","DOI":"10.1210\/mend.13.12.0392","volume":"13","author":"FH Nystrom","year":"1999","unstructured":"Nystrom, F. H., Chen, H., Cong, L. N., Li, Y. & Quon, M. J. Caveolin-1 interacts with the insulin receptor and can differentially modulate insulin signaling in transfected Cos-7 cells and rat adipose cells. Mol Endocrinol 13, 2013\u20132024, https:\/\/doi.org\/10.1210\/mend.13.12.0392 (1999).","journal-title":"Mol Endocrinol"},{"key":"32490_CR8","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.sleep.2016.06.009","volume":"25","author":"Prachi Singh","year":"2016","unstructured":"Singh, P. & Somers, V. K. Obstructive sleep apnea, diabetes, and obesity: partners in crime? Sleep Medicine, https:\/\/doi.org\/10.1016\/j.sleep.2016.06.009 (2016).","journal-title":"Sleep Medicine"},{"key":"32490_CR9","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/j.resp.2012.08.011","volume":"184","author":"JW Weiss","year":"2012","unstructured":"Weiss, J. W., Liu, Y., Li, X. & Ji, E. S. Nitric oxide and obstructive sleep apnea. Respir Physiol Neurobiol 184, 192\u2013196, https:\/\/doi.org\/10.1016\/j.resp.2012.08.011 (2012).","journal-title":"Respir Physiol Neurobiol"},{"key":"32490_CR10","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1097\/00004872-199917010-00010","volume":"17","author":"BG Phillips","year":"1999","unstructured":"Phillips, B. G. et al. Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J Hypertens 17, 61\u201366 (1999).","journal-title":"J Hypertens"},{"key":"32490_CR11","doi-asserted-by":"publisher","first-page":"40L","DOI":"10.1016\/S0002-9149(02)02963-6","volume":"90","author":"D Behrendt","year":"2002","unstructured":"Behrendt, D. & Ganz, P. Endothelial function. From vascular biology to clinical applications. The American journal of cardiology 90, 40L\u201348L (2002).","journal-title":"The American journal of cardiology"},{"key":"32490_CR12","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1073\/pnas.0406092102","volume":"102","author":"PM Bauer","year":"2005","unstructured":"Bauer, P. M. et al. Endothelial-specific expression of caveolin-1 impairs microvascular permeability and angiogenesis. Proceedings of the National Academy of Sciences of the United States of America 102, 204\u2013209, https:\/\/doi.org\/10.1073\/pnas.0406092102 (2005).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"32490_CR13","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1161\/01.HYP.37.2.511","volume":"37","author":"NL Kanagy","year":"2001","unstructured":"Kanagy, N. L., Walker, B. R. & Nelin, L. D. Role of endothelin in intermittent hypoxia-induced hypertension. Hypertension 37, 511\u2013515 (2001).","journal-title":"Hypertension"},{"key":"32490_CR14","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1152\/japplphysiol.00641.2015","volume":"120","author":"E Gras","year":"2016","unstructured":"Gras, E. et al. Endothelin-1 mediates intermittent hypoxia-induced inflammatory vascular remodeling through HIF-1 activation. J Appl Physiol (1985) 120, 437\u2013443, https:\/\/doi.org\/10.1152\/japplphysiol.00641.2015 (2016).","journal-title":"J Appl Physiol (1985)"},{"key":"32490_CR15","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1113\/expphysiol.2006.035204","volume":"92","author":"GE Foster","year":"2007","unstructured":"Foster, G. E., Poulin, M. J. & Hanly, P. J. Intermittent hypoxia and vascular function: implications for obstructive sleep apnoea. Exp Physiol 92, 51\u201365, https:\/\/doi.org\/10.1113\/expphysiol.2006.035204 (2007).","journal-title":"Exp Physiol"},{"key":"32490_CR16","doi-asserted-by":"publisher","first-page":"4892","DOI":"10.1073\/pnas.1112129109","volume":"109","author":"Y Wang","year":"2012","unstructured":"Wang, Y. et al. Hypoxia promotes ligand-independent EGF receptor signaling via hypoxia-inducible factor-mediated upregulation of caveolin-1. Proceedings of the National Academy of Sciences of the United States of America 109, 4892\u20134897, https:\/\/doi.org\/10.1073\/pnas.1112129109 (2012).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"32490_CR17","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1007\/s10456-009-9131-y","volume":"12","author":"S Toffoli","year":"2009","unstructured":"Toffoli, S. et al. Intermittent hypoxia is an angiogenic inducer for endothelial cells: role of HIF-1. Angiogenesis 12, 47\u201367, https:\/\/doi.org\/10.1007\/s10456-009-9131-y (2009).","journal-title":"Angiogenesis"},{"key":"32490_CR18","doi-asserted-by":"publisher","first-page":"E1151","DOI":"10.1152\/ajpcell.00006.2003","volume":"285","author":"AW Cohen","year":"2003","unstructured":"Cohen, A. W., Combs, T. P., Scherer, P. E. & Lisanti, M. P. Role of caveolin and caveolae in insulin signaling and diabetes. American journal of physiology 285, E1151\u20131160 (2003).","journal-title":"American journal of physiology"},{"key":"32490_CR19","doi-asserted-by":"publisher","first-page":"E134","DOI":"10.1152\/ajpendo.00498.2010","volume":"300","author":"H Wang","year":"2011","unstructured":"Wang, H., Wang, A. X. & Barrett, E. J. Caveolin-1 is required for vascular endothelial insulin uptake. American journal of physiology 300, E134\u2013144, https:\/\/doi.org\/10.1152\/ajpendo.00498.2010 (2011).","journal-title":"American journal of physiology"},{"key":"32490_CR20","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1007\/s11154-012-9229-1","volume":"14","author":"R Muniyappa","year":"2013","unstructured":"Muniyappa, R. & Sowers, J. R. Role of insulin resistance in endothelial dysfunction. Rev Endocr Metab Disord 14, 5\u201312, https:\/\/doi.org\/10.1007\/s11154-012-9229-1 (2013).","journal-title":"Rev Endocr Metab Disord"},{"key":"32490_CR21","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1161\/01.HYP.29.3.700","volume":"29","author":"M Hausberg","year":"1997","unstructured":"Hausberg, M. et al. Contrasting autonomic and hemodynamic effects of insulin in healthy elderly versus young subjects. Hypertension 29, 700\u2013705 (1997).","journal-title":"Hypertension"},{"key":"32490_CR22","doi-asserted-by":"publisher","first-page":"1899","DOI":"10.1210\/jcem.80.6.7775638","volume":"80","author":"GS Meneilly","year":"1995","unstructured":"Meneilly, G. S., Elliot, T., Bryer-Ash, M. & Floras, J. S. Insulin-mediated increase in blood flow is impaired in the elderly. J Clin Endocrinol Metab 80, 1899\u20131903, https:\/\/doi.org\/10.1210\/jcem.80.6.7775638 (1995).","journal-title":"J Clin Endocrinol Metab"},{"key":"32490_CR23","doi-asserted-by":"publisher","first-page":"30392","DOI":"10.1074\/jbc.M103702200","volume":"276","author":"M Montagnani","year":"2001","unstructured":"Montagnani, M., Chen, H., Barr, V. A. & Quon, M. J. Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser(1179). The Journal of biological chemistry 276, 30392\u201330398, https:\/\/doi.org\/10.1074\/jbc.M103702200 (2001).","journal-title":"The Journal of biological chemistry"},{"key":"32490_CR24","doi-asserted-by":"publisher","first-page":"3227","DOI":"10.1128\/MCB.00506-13","volume":"33","author":"K Park","year":"2013","unstructured":"Park, K. et al. Serine phosphorylation sites on IRS2 activated by angiotensin II and protein kinase C to induce selective insulin resistance in endothelial cells. Molecular and cellular biology 33, 3227\u20133241, https:\/\/doi.org\/10.1128\/MCB.00506-13 (2013).","journal-title":"Molecular and cellular biology"},{"key":"32490_CR25","doi-asserted-by":"publisher","first-page":"9670","DOI":"10.1074\/jbc.M007454200","volume":"276","author":"S Parpal","year":"2001","unstructured":"Parpal, S., Karlsson, M., Thorn, H. & Stralfors, P. Cholesterol depletion disrupts caveolae and insulin receptor signaling for metabolic control via insulin receptor substrate-1, but not for mitogen-activated protein kinase control. J Biol Chem 276, 9670\u20139678, https:\/\/doi.org\/10.1074\/jbc.M007454200 (2001).","journal-title":"J Biol Chem"},{"key":"32490_CR26","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1186\/s12933-015-0278-0","volume":"14","author":"V De Nigris","year":"2015","unstructured":"De Nigris, V. et al. Short-term high glucose exposure impairs insulin signaling in endothelial cells. Cardiovasc Diabetol 14, 114, https:\/\/doi.org\/10.1186\/s12933-015-0278-0 (2015).","journal-title":"Cardiovasc Diabetol"},{"key":"32490_CR27","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1160\/TH03-04-0228","volume":"90","author":"I Fleming","year":"2003","unstructured":"Fleming, I. et al. AMP-activated protein kinase (AMPK) regulates the insulin-induced activation of the nitric oxide synthase in human platelets. Thromb Haemost 90, 863\u2013871, https:\/\/doi.org\/10.1160\/TH03-04-0228 (2003).","journal-title":"Thromb Haemost"},{"key":"32490_CR28","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.atherosclerosis.2013.09.033","volume":"231","author":"MS Hoffmann","year":"2013","unstructured":"Hoffmann, M. S., Singh, P., Wolk, R., Narkiewicz, K. & Somers, V. K. Obstructive sleep apnea and intermittent hypoxia increase expression of dual specificity phosphatase 1. Atherosclerosis 231, 378\u2013383, https:\/\/doi.org\/10.1016\/j.atherosclerosis.2013.09.033 (2013).","journal-title":"Atherosclerosis"},{"key":"32490_CR29","doi-asserted-by":"publisher","first-page":"C222","DOI":"10.1152\/ajpcell.00006.2003","volume":"285","author":"AW Cohen","year":"2003","unstructured":"Cohen, A. W. et al. Caveolin-1-deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue. Am J Physiol Cell Physiol 285, C222\u2013235, https:\/\/doi.org\/10.1152\/ajpcell.00006.2003 (2003).","journal-title":"Am J Physiol Cell Physiol"},{"key":"32490_CR30","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/j.atherosclerosis.2010.10.012","volume":"217","author":"P Singh","year":"2011","unstructured":"Singh, P., Peterson, T. E., Sert-Kuniyoshi, F. H., Jensen, M. D. & Somers, V. K. Leptin upregulates caveolin-1 expression: implications for development of atherosclerosis. Atherosclerosis 217, 499\u2013502, https:\/\/doi.org\/10.1016\/j.atherosclerosis.2010.10.012 (2011).","journal-title":"Atherosclerosis"},{"key":"32490_CR31","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1136\/jim-52-02-22","volume":"52","author":"MA Lynn","year":"2004","unstructured":"Lynn, M. A. et al. Fatty acids differentially modulate insulin-stimulated endothelial nitric oxide production by an Akt-independent pathway. J Investig Med 52, 129\u2013136, https:\/\/doi.org\/10.1136\/jim-52-02-22 (2004).","journal-title":"J Investig Med"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-32490-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-32490-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-32490-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T09:43:11Z","timestamp":1671615791000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-32490-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,20]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["32490"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-32490-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,20]]},"assertion":[{"value":"26 June 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 August 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 September 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Dr. V.K.S. has received grant support from Philips Respironics Foundation (gift to Mayo Foundation) and has served as a consultant for Respicardia, ResMed, Sorin Inc., U-Health, GlaxoSmithKline, Rhonda Grey, Dane Garvin, Philips Respironics, Biosense Webster. He is also working with Mayo Health Solutions and their industry partners on intellectual property related to sleep and cardiovascular disease. All other authors declare no potential conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"14110"}}