{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T06:18:57Z","timestamp":1791872337020,"version":"4.3.4"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2021,10,23]],"date-time":"2021-10-23T00:00:00Z","timestamp":1634947200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2021,10,23]],"date-time":"2021-10-23T00:00:00Z","timestamp":1634947200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"funder":[{"DOI":"10.13039\/100000084","name":"Directorate for Engineering","doi-asserted-by":"publisher","award":["2034780"],"award-info":[{"award-number":["2034780"]}],"id":[{"id":"10.13039\/100000084","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neuroimmune Pharmacol"],"published-print":{"date-parts":[[2021,12]]},"DOI":"10.1007\/s11481-021-10029-0","type":"journal-article","created":{"date-parts":[[2021,10,23]],"date-time":"2021-10-23T04:02:45Z","timestamp":1634961765000},"page":"722-728","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":101,"title":["SARS-CoV-2 Spike Protein Disrupts Blood\u2013Brain Barrier Integrity via RhoA Activation"],"prefix":"10.1007","volume":"16","author":[{"given":"Brandon J.","family":"DeOre","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiet A.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison M.","family":"Andrews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Servio H.","family":"Ramirez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5161-4924","authenticated-orcid":false,"given":"Peter A.","family":"Galie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,23]]},"reference":[{"key":"10029_CR1","doi-asserted-by":"crossref","unstructured":"Abedi F, Hayes AW, Reiter R, Karimi G (2020a) Acute lung injury: The therapeutic role of Rho kinase inhibitors. Pharmacol\u00a0Res\u00a0155:104736","DOI":"10.1016\/j.phrs.2020.104736"},{"key":"10029_CR2","doi-asserted-by":"crossref","unstructured":"Abedi F, Rezaee R, Karimi G (2020b) Plausibility of therapeutic effects of Rho kinase inhibitors against Severe Acute Respiratory Syndrome Coronavirus 2 (COVID-19). Pharmacol Res\u00a0156:104808","DOI":"10.1016\/j.phrs.2020.104808"},{"key":"10029_CR3","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.brainres.2015.04.054","volume":"1620","author":"NK Acharya","year":"2015","unstructured":"Acharya NK, Goldwaser EL, Forsberg MM, Godsey GA, Johnson CA, Sarkar A et al (2015) Sevoflurane and Isoflurane induce structural changes in brain vascular endothelial cells and increase blood-brain barrier permeability: Possible link to postoperative delirium and cognitive decline. Brain Res 1620:29\u201341","journal-title":"Brain Res"},{"issue":"4","key":"10029_CR4","doi-asserted-by":"publisher","first-page":"251","DOI":"10.3109\/10739689409146752","volume":"1","author":"RH Adamson","year":"1994","unstructured":"Adamson RH, Lenz JF, Curry FE (1994) Quantitative laser scanning confocal microscopy on single capillaries: permeability measurement. Microcirculation 1(4):251\u2013265","journal-title":"Microcirculation"},{"issue":"1","key":"10029_CR5","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/2045-8118-10-5","volume":"10","author":"K Benson","year":"2013","unstructured":"Benson K, Cramer S, Galla HJ (2013) Impedance-based cell monitoring: barrier properties and beyond. Fluids Barriers CNS 10(1):5","journal-title":"Fluids Barriers CNS"},{"key":"10029_CR6","doi-asserted-by":"crossref","unstructured":"Bouhrira N, Deore BJ, Sazer DW, Chiaradia Z, Miller JS, Galie PA (2019) Disturbed flow disrupts the blood-brain barrier in a 3D bifurcation model. Biofabrication","DOI":"10.1088\/1758-5090\/ab5898"},{"key":"10029_CR7","doi-asserted-by":"crossref","unstructured":"Buzhdygan TP, Deore BJ, Baldwin-Leclair A, Bullock TA, Mcgary HM, Khan JA et al (2020) The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier. Neurobiol Dis\u00a0146:105131","DOI":"10.1016\/j.nbd.2020.105131"},{"key":"10029_CR8","doi-asserted-by":"crossref","unstructured":"Chaudhry F, Lavandero S, Xie X, Sabharwal B, Zheng YY, Correa A et al (2020) Manipulation of ACE2 expression in COVID-19. Open Heart 7(2)","DOI":"10.1136\/openhrt-2020-001424"},{"issue":"2","key":"10029_CR9","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1007\/s11481-021-09986-3","volume":"16","author":"AJM Chaves Filho","year":"2021","unstructured":"Chaves Filho AJM, Gon\u00e7alves F, Mottin M, Andrade CH, Fonseca SNS, Macedo DS (2021) Repurposing of Tetracyclines for COVID-19 Neurological and Neuropsychiatric Manifestations: A Valid Option to Control SARS-CoV-2-Associated Neuroinflammation?. J Neuroimmune Pharmacol 16(2):213\u2013218","journal-title":"J Neuroimmune Pharmacol"},{"issue":"4","key":"10029_CR10","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1038\/nrm1357","volume":"5","author":"E Dejana","year":"2004","unstructured":"Dejana E (2004) Endothelial cell-cell junctions: happy together. Nat Rev Mol Cell Biol 5(4):261\u2013270","journal-title":"Nat Rev Mol Cell Biol"},{"key":"10029_CR12","doi-asserted-by":"crossref","unstructured":"Kimura K, Eguchi S (2009) Angiotensin II type-1 receptor regulates RhoA and Rho-kinase\/ROCK activation via multiple mechanisms. Focus on \"Angiotensin II induces RhoA activation through SHP2-dependent dephosphorylation of the RhoGAP p190A in vascular smooth muscle cells\". Am J Physiol Cell Physiol 297(5):C1059\u20131061","DOI":"10.1152\/ajpcell.00399.2009"},{"key":"10029_CR13","doi-asserted-by":"crossref","unstructured":"Kumar A, Narayan RK, Kumari C, Faiq MA, Kulandhasamy M, Kant K et al (2020) SARS-CoV-2 cell entry receptor ACE2 mediated endothelial dysfunction leads to vascular thrombosis in COVID-19 patients. Med Hypotheses 145:110320","DOI":"10.1016\/j.mehy.2020.110320"},{"issue":"2","key":"10029_CR14","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/j.febslet.2007.11.085","volume":"582","author":"DW Lambert","year":"2008","unstructured":"Lambert DW, Clarke NE, Hooper NM, Turner AJ (2008) Calmodulin interacts with angiotensin-converting enzyme-2 (ACE2) and inhibits shedding of its ectodomain. FEBS Lett 582(2):385\u2013390","journal-title":"FEBS Lett"},{"key":"10029_CR15","doi-asserted-by":"publisher","first-page":"6725","DOI":"10.1038\/ncomms7725","volume":"6","author":"CM Mikelis","year":"2015","unstructured":"Mikelis CM, Simaan M, Ando K, Fukuhara S, Sakurai A, Amornphimoltham P et al (2015) RhoA and ROCK mediate histamine-induced vascular leakage and anaphylactic shock. Nat Commun 6:6725","journal-title":"Nat Commun"},{"issue":"4","key":"10029_CR16","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1038\/s41591-021-01283-z","volume":"27","author":"A Nalbandian","year":"2021","unstructured":"Nalbandian A, Sehgal K, Gupta A, Madhavan MV, Mcgroder C, Stevens JS et al (2021) Post-acute COVID-19 syndrome. Nat Med 27(4):601\u2013615","journal-title":"Nat Med"},{"issue":"1","key":"10029_CR17","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1186\/s13054-020-03120-0","volume":"24","author":"W Ni","year":"2020","unstructured":"Ni W, Yang X, Yang D, Bao J, Li R, Xiao Y et al (2020) Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Crit Care 24(1):422","journal-title":"Crit Care"},{"issue":"4","key":"10029_CR18","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1093\/ageing\/afaa094","volume":"49","author":"S O'hanlon","year":"2020","unstructured":"O\u2019hanlon S, Inouye SK (2020) Delirium: a missing piece in the COVID-19 pandemic puzzle. Age Ageing 49(4):497\u2013498","journal-title":"Age Ageing"},{"key":"10029_CR19","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.biomaterials.2016.11.012","volume":"115","author":"PP Partyka","year":"2017","unstructured":"Partyka PP, Godsey GA, Galie JR, Kosciuk MC, Acharya NK, Nagele RG et al (2017) Mechanical stress regulates transport in a compliant 3D model of the blood-brain barrier. Biomaterials 115:30\u201339","journal-title":"Biomaterials"},{"issue":"4","key":"10029_CR20","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1093\/infdis\/jiaa332","volume":"222","author":"BGG Pinto","year":"2020","unstructured":"Pinto BGG, Oliveira AER, Singh Y, Jimenez L, Goncalves ANA, Ogava RLT et al (2020) ACE2 Expression Is Increased in the Lungs of Patients With Comorbidities Associated With Severe COVID-19. J Infect Dis 222(4):556\u2013563","journal-title":"J Infect Dis"},{"key":"10029_CR21","doi-asserted-by":"crossref","unstructured":"Qin Y, Wu J, Chen T, Li J, Zhang G, Wu D et al (2021) Long-term microstructure and cerebral blood flow changes in patients recovered from COVID-19 without neurological manifestations.\u00a0J\u00a0Clin\u00a0Investig\u00a0131(8)","DOI":"10.1172\/JCI147329"},{"issue":"1","key":"10029_CR22","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1007\/s11481-020-09975-y","volume":"16","author":"JL Reynolds","year":"2021","unstructured":"Reynolds JL, Mahajan SD (2021) SARS-COV2 Alters Blood Brain Barrier Integrity Contributing to Neuro-Inflammation. J Neuroimmune Pharmacol 16(1):4\u20136","journal-title":"J Neuroimmune Pharmacol"},{"issue":"6","key":"10029_CR23","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1161\/HYPERTENSIONAHA.113.01274","volume":"63","author":"RA Santos","year":"2014","unstructured":"Santos RA (2014) Angiotensin-(1\u20137). Hypertension 63(6):1138\u20131147","journal-title":"Hypertension"},{"issue":"2","key":"10029_CR24","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1091\/mbc.9.2.403","volume":"9","author":"RJ Shaw","year":"1998","unstructured":"Shaw RJ, Henry M, Solomon F, Jacks T (1998) RhoA-dependent phosphorylation and relocalization of ERM proteins into apical membrane\/actin protrusions in fibroblasts. Mol Biol Cell 9(2):403\u2013419","journal-title":"Mol Biol Cell"},{"issue":"1","key":"10029_CR25","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.jns.2005.06.003","volume":"238","author":"M Shibuya","year":"2005","unstructured":"Shibuya M, Hirai S, Seto M, Satoh S-I, Ohtomo E (2005) Effects of fasudil in acute ischemic stroke: Results of a prospective placebo-controlled double-blind trial. J Neurol Sci 238(1):31\u201339","journal-title":"J Neurol Sci"},{"issue":"3","key":"10029_CR26","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1016\/j.bbrc.2020.02.151","volume":"525","author":"J Song","year":"2020","unstructured":"Song J, Hu B, Qu H, Wang L, Huang X, Li M et al (2020) Upregulation of angiotensin converting enzyme 2 by shear stress reduced inflammation and proliferation in vascular endothelial cells. Biochem Biophys Res Commun 525(3):812\u2013818","journal-title":"Biochem Biophys Res Commun"},{"issue":"13","key":"10029_CR27","doi-asserted-by":"publisher","first-page":"1872","DOI":"10.1096\/fj.04-3458fje","volume":"19","author":"BB Weksler","year":"2005","unstructured":"Weksler BB, Subileau EA, Perriere N, Charneau P, Holloway K, Leveque M et al (2005) Blood-brain barrier-specific properties of a human adult brain endothelial cell line. FASEB J 19(13):1872\u20131874","journal-title":"FASEB J"},{"issue":"6","key":"10029_CR28","doi-asserted-by":"publisher","first-page":"1482","DOI":"10.1111\/j.1471-4159.2008.05723.x","volume":"107","author":"H Xia","year":"2008","unstructured":"Xia H, Lazartigues E (2008) Angiotensin-converting enzyme 2 in the brain: properties and future directions. J Neurochem 107(6):1482\u20131494","journal-title":"J Neurochem"},{"key":"10029_CR29","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.thromres.2019.02.016","volume":"176","author":"X Xu","year":"2019","unstructured":"Xu X, Shi L, Ma X, Su H, Ma G, Wu X et al (2019) RhoA-Rho associated kinase signaling leads to renin-angiotensin system imbalance and angiotensin converting enzyme 2 has a protective role in acute pulmonary embolism. Thromb Res 176:85\u201394","journal-title":"Thromb Res"},{"issue":"2","key":"10029_CR30","doi-asserted-by":"publisher","first-page":"521","DOI":"10.2353\/ajpath.2008.070076","volume":"172","author":"M Yamamoto","year":"2008","unstructured":"Yamamoto M, Ramirez SH, Sato S, Kiyota T, Cerny RL, Kaibuchi K et al (2008) Phosphorylation of Claudin-5 and Occludin by Rho Kinase in Brain Endothelial Cells. Am J Pathol 172(2):521\u2013533","journal-title":"Am J Pathol"},{"issue":"3","key":"10029_CR31","doi-asserted-by":"publisher","first-page":"1873","DOI":"10.1111\/jcmm.13471","volume":"22","author":"C Zhang","year":"2018","unstructured":"Zhang C, Wang J, Ma X, Wang W, Zhao B, Chen Y et al (2018) ACE2-EPC-EXs protect ageing ECs against hypoxia\/reoxygenation-induced injury through the miR-18a\/Nox2\/ROS pathway. J Cell Mol Med 22(3):1873\u20131882","journal-title":"J Cell Mol Med"}],"container-title":["Journal of Neuroimmune Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11481-021-10029-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11481-021-10029-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11481-021-10029-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T08:09:30Z","timestamp":1640765370000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11481-021-10029-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,23]]},"references-count":30,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["10029"],"URL":"https:\/\/doi.org\/10.1007\/s11481-021-10029-0","relation":{},"ISSN":["1557-1890","1557-1904"],"issn-type":[{"value":"1557-1890","type":"print"},{"value":"1557-1904","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,23]]},"assertion":[{"value":"1 June 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 October 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 October 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors report no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}},{"value":"This content has been made available to all.","name":"free","label":"Free to read"}]}}