{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T00:43:36Z","timestamp":1792197816697,"version":"4.4.0"},"reference-count":56,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T00:00:00Z","timestamp":1775865600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T00:00:00Z","timestamp":1775865600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/W027119\/1"],"award-info":[{"award-number":["MR\/W027119\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017510","name":"UK Dementia Research Institute","doi-asserted-by":"publisher","award":["UK DRI\u20108203"],"award-info":[{"award-number":["UK DRI\u20108203"]}],"id":[{"id":"10.13039\/501100017510","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000769","name":"University of Oxford","doi-asserted-by":"publisher","award":["RE\/24\/130024"],"award-info":[{"award-number":["RE\/24\/130024"]}],"id":[{"id":"10.13039\/501100000769","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":[[2026,7]]},"abstract":"\n Abstract<\/jats:title>\n \n A functional blood\u2013brain barrier (BBB) is essential for CNS homeostasis, and its disruption is an early feature of both acute brain injury and chronic neurodegenerative disorders. Hypoxia induces BBB breakdown by triggering endothelial dysfunction, oxidative stress, metabolic dysregulation and thrombo\u2010inflammatory signalling that compromise barrier integrity. However, strategies that restore BBB function remain limited. Here, we investigated whether photobiomodulation (PBM), a non\u2010invasive light therapy, can rescue BBB dysfunction following acute hypoxic stress. Using a multicellular\n in vitro<\/jats:italic>\n BBB model comprising immortalised human brain microvascular endothelial cells, pericytes and astrocytes, we induced hypoxic injury (6\u00a0h, 1% O\n 2<\/jats:sub>\n ) and applied three PBM treatments during recovery. Hypoxia significantly reduced transendothelial electrical resistance (TEER), whereas PBM restored barrier function in endothelial monocultures and tri\u2010cultures. Endothelial cells exhibited the most pronounced hypoxic response, characterised by increased expression of hypoxia\u2010inducible factor\u20101\u03b1 (HIF\u20101\u03b1), plasminogen activator inhibitor\u20101 and von Willebrand factor (vWF), all attenuated by PBM. Importantly, small interfering RNA\u2010mediated knockdown of vWF partially recapitulated PBM\u2010induced restoration of barrier integrity, identifying endothelial vWF as a mediator of recovery. PBM also reduced reactive oxygen species in hypoxic astrocytes and pericytes, indicating co\u2010ordinated multicellular modulation. Together, these findings demonstrate that PBM restores BBB integrity following hypoxic insult by modulating endothelial thrombo\u2010inflammatory signalling at the same time as reducing oxidative stress in glial cells. Rather than acting as a non\u2010specific cytoprotective stimulus, PBM engages molecular pathways linked to endothelial activation. This work establishes a mechanistically informed platform for investigating BBB repair and highlights PBM as a strategy to protect vascular integrity in hypoxia\u2010associated neurological disorders.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Hypoxia is a major driver of blood\u2013brain barrier (BBB) dysfunction, yet there are currently no targeted therapies that directly restore barrier integrity.<\/jats:p>\n <\/jats:list-item>\n \n Photobiomodulation (PBM) is a non\u2010invasive low\u2010level light intervention known to facilitate mitochondrial function and cellular stress responses.<\/jats:p>\n <\/jats:list-item>\n \n \n In a human\n in vitro<\/jats:italic>\n BBB model, repeated PBM treatment restored transendothelial electrical resistance (TEER) 24 and 48\u00a0h after hypoxic injury, with endothelial rescue linked to downregulation of von Willebrand factor (vWF).\n <\/jats:p>\n <\/jats:list-item>\n \n PBM modulated oxidative stress, hypoxia signalling and thrombo\u2010inflammatory pathways across endothelial cells, astrocytes and pericytes.<\/jats:p>\n <\/jats:list-item>\n \n These findings support PBM\u2010driven modulation of endothelial signalling as a potential strategy to restore BBB integrity in hypoxia\u2010associated neurological conditions.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp291064","type":"journal-article","created":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T02:43:36Z","timestamp":1775961816000},"page":"6080-6103","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Photobiomodulation restores blood\u2013brain barrier integrity after hypoxia via endothelial von Willebrand factor modulation in a humanised tricellular transwell model"],"prefix":"10.1113","volume":"604","author":[{"given":"Mirriam","family":"Domocos","sequence":"first","affiliation":[{"name":"Department of Physiology, Anatomy, and Genetics University of Oxford Oxford UK"},{"name":"British Heart Foundation (BHF) Oxford Centre of Research Excellence University of Oxford Oxford UK"},{"name":"Kavli Institute for NanoScience Discovery University of Oxford Oxford UK"},{"name":"British Heart Foundation (BHF)\u00a0\u2013\u00a0UK Dementia Research Institute (UK DRI) Centre for Vascular Dementia Research University of Oxford Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis E.","family":"Bragin","sequence":"additional","affiliation":[{"name":"Lovelace Biomedical Research Institute Albuquerque NM USA"},{"name":"Department of Neurology University of New Mexico School of Medicine Albuquerque NM USA"},{"name":"Department of Cell and Molecular Physiology New York Medical College Valhalla NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagesh C.","family":"Shanbhag","sequence":"additional","affiliation":[{"name":"Meditech Foundation Cali Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luise","family":"Schlotterose","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy, and Genetics University of Oxford Oxford UK"},{"name":"British Heart Foundation (BHF) Oxford Centre of Research Excellence University of Oxford Oxford UK"},{"name":"Kavli Institute for NanoScience Discovery University of Oxford Oxford UK"},{"name":"British Heart Foundation (BHF)\u00a0\u2013\u00a0UK Dementia Research Institute (UK DRI) Centre for Vascular Dementia Research University of Oxford Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mootaz M.","family":"Salman","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy, and Genetics University of Oxford Oxford UK"},{"name":"British Heart Foundation (BHF) Oxford Centre of Research Excellence University of Oxford Oxford UK"},{"name":"Kavli Institute for NanoScience Discovery University of Oxford Oxford UK"},{"name":"British Heart Foundation (BHF)\u00a0\u2013\u00a0UK Dementia Research Institute (UK DRI) Centre for Vascular Dementia Research University of Oxford Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,11]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202202944"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mvr.2012.05.008"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP284197"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.4103\/NRR.NRR-D-24-01013"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-803726-3.00004-3"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2007.02768.x"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1089\/photob.2018.4555"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jphotobiol.2020.111935"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2008.12.010"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9030274"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-014-1811-2"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12489"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.24544"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1242\/bio.059371"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/5620314"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.3934\/biophy.2017.3.337"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/php.12864"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.regpep.2004.05.023"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.717550"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-024-01484-x"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0047460"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1011-1344(98)00219-X"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.13696"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2006.02.002"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.03.003"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12987-025-00688-z"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.6.3369"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2219091120"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1815-1"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-16927-9"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-025-01787-7"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X16666180110130253"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1101\/2025.10.15.682687"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s10020-020-00163-5"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21207448"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202502849R"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/trf.15667"},{"issue":"57","key":"e_1_2_6_39_1","first-page":"154","article-title":"Therapeutic photobiomodulation: Nitric oxide and a novel function of mitochondrial cytochrome c oxidase","volume":"11","author":"Poyton R. O.","year":"2011","journal-title":"Discovery Medicine"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190062"},{"key":"e_1_2_6_41_1","first-page":"49","article-title":"Low\u2010level light therapy of the eye and brain","volume":"3","author":"Rojas J. C.","year":"2011","journal-title":"Eye Brain"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaf068"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom10040610"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-017-0852-4"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab311"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2017.00386"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25042078"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.113.301362"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/lsm.22343"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.117.309451"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12085"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M409650200"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01481-w"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.70107"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X241311695"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000001690"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep35901"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP291064","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP291064","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP291064","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T07:35:09Z","timestamp":1785742509000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP291064"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,11]]},"references-count":56,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1113\/JP291064"],"URL":"https:\/\/doi.org\/10.1113\/jp291064","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,11]]},"assertion":[{"value":"2026-02-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}