{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:17:48Z","timestamp":1793038668164,"version":"4.5.0"},"reference-count":117,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T00:00:00Z","timestamp":1677110400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000383","name":"Higher Education Funding Council for Wales","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000383","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["107544\/Z\/15\/Z"],"award-info":[{"award-number":["107544\/Z\/15\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>High\u2010altitude (HA) hypoxia may alter the structural\u2013functional integrity of the neurovascular unit (NVU). Herein, we compared male lowlanders (<jats:italic>n<\/jats:italic>\u00a0=\u00a09) at sea level (SL) and after 14\u00a0days acclimatization to 4300\u00a0m (chronic HA) in Cerro de Pasco (CdP), P\u00e9ru (HA), against sex\u2010, age\u2010 and body mass index\u2010matched healthy highlanders (<jats:italic>n<\/jats:italic>\u00a0=\u00a09) native to CdP (lifelong HA). Venous blood was assayed for serum proteins reflecting NVU integrity, in addition to free radicals and nitric oxide (NO). Regional cerebral blood flow (CBF) was examined in conjunction with cerebral substrate delivery, dynamic cerebral autoregulation (dCA), cerebrovascular reactivity to carbon dioxide (CVR<jats:sub>CO2<\/jats:sub>) and neurovascular coupling (NVC). Psychomotor tests were employed to examine cognitive function. Compared to lowlanders at SL, highlanders exhibited elevated basal plasma and red blood cell NO bioavailability, improved anterior and posterior dCA, elevated anterior CVR<jats:sub>CO2<\/jats:sub> and preserved cerebral substrate delivery, NVC and cognition. In highlanders, S100B, neurofilament light\u2010chain (NF\u2010L) and T\u2010tau were consistently lower and cognition comparable to lowlanders following chronic\u2010HA. These findings highlight novel integrated adaptations towards regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15416-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>High\u2010altitude (HA) hypoxia has the potential to alter the structural\u2013functional integrity of the neurovascular unit (NVU) in humans.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>For the first time, we examined to what extent chronic and lifelong hypoxia impacts multimodal biomarkers reflecting NVU structure and function in lowlanders and native Andean highlanders.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Despite lowlanders presenting with a reduction in systemic oxidative\u2013nitrosative stress and maintained cerebral bioenergetics and cerebrovascular function during chronic hypoxia, there was evidence for increased axonal injury and cognitive impairment.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Compared to lowlanders at sea level, highlanders exhibited elevated vascular NO bioavailability, improved dynamic regulatory capacity and cerebrovascular reactivity, comparable cerebral substrate delivery and neurovascular coupling, and maintained cognition. Unlike lowlanders following chronic HA, highlanders presented with lower concentrations of S100B, neurofilament light chain and total tau.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These findings highlight novel integrated adaptations towards the regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp283362","type":"journal-article","created":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T14:33:23Z","timestamp":1673534003000},"page":"1095-1120","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Lifelong exposure to high\u2010altitude hypoxia in humans is associated with improved redox homeostasis and structural\u2013functional adaptations of the neurovascular 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