{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T23:45:06Z","timestamp":1787960706414,"version":"build-2784847793"},"reference-count":48,"publisher":"Portland Press Ltd.","issue":"21","license":[{"start":{"date-parts":[[2024,10,2]],"date-time":"2024-10-02T00:00:00Z","timestamp":1727827200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R01 NS104573"],"award-info":[{"award-number":["R01 NS104573"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"crossref","award":["BX000347"],"award-info":[{"award-number":["BX000347"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"crossref","award":["IK6 BX004471"],"award-info":[{"award-number":["IK6 BX004471"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,11,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Endothelin-1 (ET-1), the most potent vasoconstrictor identified to date, contributes to cerebrovascular dysfunction. ET-1 levels in postmortem brain specimens from individuals diagnosed with Alzheimer\u2019s disease (AD) and related dementias (ADRD) were shown to be related to cerebral hypoxia and disease severity. ET-1-mediated vascular dysfunction and ensuing cognitive deficits have also been reported in experimental models of AD and ADRD. Moreover, studies also showed that ET-1 secreted from brain microvascular endothelial cells (BMVECs) can affect neurovascular unit integrity in an autocrine and paracrine manner. Vascular contributions to cognitive impairment and dementia (VCID) is a leading ADRD cause known to be free of neuronal tau pathology, a hallmark of AD. However, a recent study reported cytotoxic hyperphosphorylated tau (p-tau) accumulation, which fails to bind or stabilize microtubules in BMVECs in VCID. Thus, the study aimed to determine the impact of ET-1 on tau pathology, microtubule organization, and barrier function in BMVECs. Cells were stimulated with 1 \u03bcM ET-1 for 24 h in the presence\/absence of ETA (BQ123; 20 \u03bcM) or ETB (BQ788; 20 \u03bcM) receptor antagonists. Cell lysates were assayed for an array of phosphorylation site-specific antibodies and microtubule organization\/stabilization markers. ET-1 stimulation increased p-tau Thr231 but decreased p-tau Ser199, Ser262, Ser396, and Ser214 levels only in the presence of ETA or ETB antagonism. ET-1 also impaired barrier function in the presence of ETA antagonism. These novel findings suggest that (1) dysregulation of endothelial tau phosphorylation may contribute to cerebral microvascular dysfunction and (2) the ET system may be an early intervention target to prevent hyperphosphorylated tau-mediated disruption of BMVEC barrier function.<\/jats:p>","DOI":"10.1042\/cs20240616","type":"journal-article","created":{"date-parts":[[2024,10,2]],"date-time":"2024-10-02T15:59:26Z","timestamp":1727884766000},"page":"1329-1341","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Complex regulation of tau phosphorylation by the endothelin system in brain microvascular endothelial cells (BMVECs): link to barrier function"],"prefix":"10.1042","volume":"138","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4156-3785","authenticated-orcid":false,"given":"Eda","family":"Karakaya","sequence":"first","affiliation":[{"name":"1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, U.S.A."},{"name":"2Ralph H. Johnson Veterans Affairs Health Care System, Charleston, SC, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasir","family":"Abdul","sequence":"additional","affiliation":[{"name":"1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, U.S.A."},{"name":"2Ralph H. Johnson Veterans Affairs Health Care System, Charleston, SC, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jazlyn","family":"Edwards","sequence":"additional","affiliation":[{"name":"1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Jamil","sequence":"additional","affiliation":[{"name":"1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, U.S.A."},{"name":"2Ralph H. Johnson Veterans Affairs Health Care System, Charleston, SC, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Onder","family":"Albayram","sequence":"additional","affiliation":[{"name":"1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, U.S.A."},{"name":"3Department of Neurosciences, Medical University of South Carolina, Charleston, SC, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0873-6015","authenticated-orcid":false,"given":"Adviye","family":"Ergul","sequence":"additional","affiliation":[{"name":"1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, U.S.A."},{"name":"2Ralph H. Johnson Veterans Affairs Health Care System, Charleston, SC, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2024,10,24]]},"reference":[{"key":"2024102405354680900_B1","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1007\/s10571-016-0334-7","article-title":"The science of vascular contributions to cognitive impairment and dementia (VCID): a framework for advancing research priorities in the cerebrovascular biology of cognitive decline","volume":"36","author":"Corriveau","year":"2016","journal-title":"Cell. Mol. Neurobiol."},{"key":"2024102405354680900_B2","doi-asserted-by":"publisher","first-page":"1714","DOI":"10.1002\/alz.12157","article-title":"Vascular contributions to cognitive impairment and dementia (VCID): A report from the 2018 National Heart, Lung, and Blood Institute and National Institute of Neurological Disorders and Stroke Workshop","volume":"16","author":"Zlokovic","year":"2020","journal-title":"Alzheimers Dement."},{"key":"2024102405354680900_B3","doi-asserted-by":"publisher","first-page":"e284","DOI":"10.1161\/STR.0000000000000148","article-title":"Defining optimal brain health in adults: a presidential advisory from the American Heart Association\/American Stroke Association","volume":"48","author":"Gorelick","year":"2017","journal-title":"Stroke"},{"key":"2024102405354680900_B4","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/j.neuron.2020.06.024","article-title":"A novel neurovascular liaison governing the blood-brain barrier","volume":"107","author":"Ishii","year":"2020","journal-title":"Neuron"},{"key":"2024102405354680900_B5","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaz7615","article-title":"Cis P-tau underlies vascular contribution to cognitive impairment and dementia and can be effectively targeted by immunotherapy in mice","volume":"13","author":"Qiu","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"2024102405354680900_B6","doi-asserted-by":"publisher","first-page":"102027","DOI":"10.1016\/j.arr.2023.102027","article-title":"Alzheimer's disease and its related dementias in US Native Americans: a major public health concern","volume":"90","author":"Sehar","year":"2023","journal-title":"Ageing Res. Rev."},{"key":"2024102405354680900_B7","doi-asserted-by":"publisher","first-page":"1858","DOI":"10.1073\/pnas.72.5.1858","article-title":"A protein factor essential for microtubule assembly","volume":"72","author":"Weingarten","year":"1975","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2024102405354680900_B8","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1016\/j.tcb.2019.02.007","article-title":"Tau: it's not what you think","volume":"29","author":"Baas","year":"2019","journal-title":"Trends Cell Biol."},{"key":"2024102405354680900_B9","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1126\/science.1132814","article-title":"A century of Alzheimer\u2019s disease","volume":"314","author":"Goedert","year":"2006","journal-title":"Science"},{"key":"2024102405354680900_B10","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/nrn.2015.1","article-title":"Tau in physiology and pathology","volume":"17","author":"Wang","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"2024102405354680900_B11","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1016\/j.neuron.2013.10.008","article-title":"The pathobiology of vascular dementia","volume":"80","author":"Iadecola","year":"2013","journal-title":"Neuron"},{"key":"2024102405354680900_B12","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1038\/nrn.2017.48","article-title":"Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease","volume":"18","author":"Kisler","year":"2017","journal-title":"Nat. Rev. Neurosci."},{"key":"2024102405354680900_B13","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1038\/s41467-017-01068-4","article-title":"Cis P-tau is induced in clinical and preclinical brain injury and contributes to post-injury sequelae","volume":"8","author":"Albayram","year":"2017","journal-title":"Nat. Commun."},{"key":"2024102405354680900_B14","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1038\/nature14658","article-title":"Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy","volume":"523","author":"Kondo","year":"2015","journal-title":"Nature"},{"key":"2024102405354680900_B15","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1161\/ATVBAHA.118.311906","article-title":"Brain vasculature and cognition","volume":"39","author":"Fouda","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2024102405354680900_B16","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/332411a0","article-title":"A novel potent vasoconstrictor peptide produced by vascular endothelial cells","volume":"332","author":"Yanagisawa","year":"1988","journal-title":"Nature"},{"key":"2024102405354680900_B17","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1124\/pr.115.011833","article-title":"Endothelin","volume":"68","author":"Davenport","year":"2016","journal-title":"Pharmacol. Rev."},{"key":"2024102405354680900_B18","doi-asserted-by":"publisher","first-page":"853","DOI":"10.3233\/JAD-2012-111760","article-title":"Endothelin-1 is elevated in Alzheimer\u2019s disease and upregulated by amyloid-\u03b2","volume":"29","author":"Palmer","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"2024102405354680900_B19","doi-asserted-by":"publisher","first-page":"1869","DOI":"10.1093\/brain\/awab094","article-title":"Systemic infection exacerbates cerebrovascular dysfunction in Alzheimer\u2019s disease","volume":"144","author":"Asby","year":"2021","journal-title":"Brain"},{"key":"2024102405354680900_B20","doi-asserted-by":"publisher","first-page":"2451","DOI":"10.1042\/CS20160727","article-title":"Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia","volume":"131","author":"Duncombe","year":"2017","journal-title":"Clin. Sci. (Lond.)"},{"key":"2024102405354680900_B21","doi-asserted-by":"publisher","first-page":"e12935","DOI":"10.1111\/bpa.12935","article-title":"Mediators of cerebral hypoperfusion and blood-brain barrier leakiness in Alzheimer\u2019s disease, vascular dementia and mixed dementia","volume":"31","author":"Tayler","year":"2021","journal-title":"Brain Pathol."},{"key":"2024102405354680900_B22","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1093\/brain\/awv025","article-title":"Post-mortem assessment of hypoperfusion of cerebral cortex in Alzheimer\u2019s disease and vascular dementia","volume":"138","author":"Thomas","year":"2015","journal-title":"Brain"},{"key":"2024102405354680900_B23","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav9518","article-title":"Amyloid \u03b2 oligomers constrict human capillaries in Alzheimer\u2019s disease via signaling to pericytes","volume":"365","author":"Nortley","year":"2019","journal-title":"Science"},{"key":"2024102405354680900_B24","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1097\/00004647-199704000-00012","article-title":"Endothelin-1 as a mediator of endothelial cell-pericyte interactions in bovine brain capillaries","volume":"17","author":"Dehouck","year":"1997","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"2024102405354680900_B25","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/2045-8118-10-33","article-title":"Comparative study of four immortalized human brain capillary endothelial cell lines, hCMEC\/D3, hBMEC, TY10, and BB19, and optimization of culture conditions, for an in vitro blood-brain barrier model for drug permeability studies","volume":"10","author":"Eigenmann","year":"2013","journal-title":"Fluids Barriers CNS"},{"key":"2024102405354680900_B26","doi-asserted-by":"publisher","first-page":"1358","DOI":"10.1111\/j.1471-4159.2008.05730.x","article-title":"The human brain endothelial cell line hCMEC\/D3 as a human blood-brain barrier model for drug transport studies","volume":"107","author":"Poller","year":"2008","journal-title":"J. Neurochem."},{"key":"2024102405354680900_B27","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.ijpharm.2018.09.040","article-title":"Assessment of HBEC-5i endothelial cell line cultivated in astrocyte conditioned medium as a human blood-brain barrier model for ABC drug transport studies","volume":"551","author":"Puech","year":"2018","journal-title":"Int. J. Pharm."},{"key":"2024102405354680900_B28","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.4049\/jimmunol.176.2.1180","article-title":"TGF-beta1 released from activated platelets can induce TNF-stimulated human brain endothelium apoptosis: a new mechanism for microvascular lesion during cerebral malaria","volume":"176","author":"Wassmer","year":"2006","journal-title":"J. Immunol."},{"key":"2024102405354680900_B29","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/2045-8118-10-16","article-title":"The hCMEC\/D3 cell line as a model of the human blood brain barrier","volume":"10","author":"Weksler","year":"2013","journal-title":"Fluids Barriers CNS"},{"key":"2024102405354680900_B30","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.1002\/alz.13016","article-title":"2023 Alzheimer\u2019s disease facts and figures","volume":"19","year":"2023","journal-title":"Alzheimers Dementia"},{"key":"2024102405354680900_B31","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1161\/CIRCRESAHA.118.311378","article-title":"Mechanisms of vascular aging","volume":"123","author":"Ungvari","year":"2018","journal-title":"Circ. Res."},{"key":"2024102405354680900_B32","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1002\/alz.12694","article-title":"Global estimates on the number of persons across the Alzheimer's disease continuum","volume":"19","author":"Gustavsson","year":"2023","journal-title":"Alzheimers Dementia"},{"issue":"1","key":"2024102405354680900_B33","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1556\/2060.2022.00020","article-title":"Contribution of cerebral microvascular mechanisms to age-related cognitive impairment and dementia","volume":"109","author":"Fang","year":"2022","journal-title":"Physiol Int."},{"key":"2024102405354680900_B34","doi-asserted-by":"publisher","DOI":"10.3390\/metabo12090826","article-title":"A review of oxylipins in Alzheimer's disease and related dementias (ADRD): potential therapeutic targets for the modulation of vascular tone and inflammation","volume":"12","author":"Shinto","year":"2022","journal-title":"Metabolites"},{"key":"2024102405354680900_B35","doi-asserted-by":"publisher","first-page":"1524","DOI":"10.1093\/brain\/awu040","article-title":"Pathophysiology of white matter perfusion in Alzheimer\u2019s disease and vascular dementia","volume":"137","author":"Barker","year":"2014","journal-title":"Brain"},{"key":"2024102405354680900_B36","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1038\/jcbfm.2015.79","article-title":"Hypertension enhances Abeta-induced neurovascular dysfunction, promotes beta-secretase activity, and leads to amyloidogenic processing of APP","volume":"36","author":"Faraco","year":"2016","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"2024102405354680900_B37","doi-asserted-by":"publisher","first-page":"2367","DOI":"10.1038\/s41467-023-37840-y","article-title":"Soluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy","volume":"14","author":"Hussong","year":"2023","journal-title":"Nat. Commun."},{"key":"2024102405354680900_B38","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1186\/s13024-017-0229-1","article-title":"A validated antibody panel for the characterization of tau post-translational modifications","volume":"12","author":"Ercan","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"2024102405354680900_B39","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241813676","article-title":"Novel conformation-dependent tau antibodies are modulated by adjacent phosphorylation sites","volume":"24","author":"Paterno","year":"2023","journal-title":"Int. J. Mol. Sci."},{"issue":"1","key":"2024102405354680900_B40","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-024-02729-7","article-title":"Validation of Tau antibodies for use in western blotting and immunohistochemistry","volume":"147","author":"Ellis","year":"2023","journal-title":"bioRxiv"},{"key":"2024102405354680900_B41","doi-asserted-by":"publisher","first-page":"30851","DOI":"10.1074\/jbc.M110.110957","article-title":"Phosphorylation of tau at Thr212, Thr231, and Ser262 combined causes neurodegeneration","volume":"285","author":"Alonso","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2024102405354680900_B42","doi-asserted-by":"publisher","first-page":"2003","DOI":"10.1016\/j.febslet.2014.04.021","article-title":"Site-specific phosphorylation of Tau protein is associated with deacetylation of microtubules in mouse spermatogenic cells during meiosis","volume":"588","author":"Inoue","year":"2014","journal-title":"FEBS Lett."},{"key":"2024102405354680900_B43","doi-asserted-by":"publisher","first-page":"595532","DOI":"10.3389\/fneur.2020.595532","article-title":"Tau post-translational modifications: dynamic transformers of tau function, degradation, and aggregation","volume":"11","author":"Alquezar","year":"2020","journal-title":"Front Neurol."},{"key":"2024102405354680900_B44","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1038\/nrn2194","article-title":"Tau-mediated neurodegeneration in Alzheimer\u2019s disease and related disorders","volume":"8","author":"Ballatore","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"2024102405354680900_B45","doi-asserted-by":"publisher","first-page":"L493","DOI":"10.1152\/ajplung.00431.2009","article-title":"Protein kinase A phosphorylation of tau-serine 214 reorganizes microtubules and disrupts the endothelial cell barrier","volume":"299","author":"Zhu","year":"2010","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2024102405354680900_B46","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/S0006-8993(98)00407-7","article-title":"The interrelationship between selective tau phosphorylation and microtubule association","volume":"798","author":"Xie","year":"1998","journal-title":"Brain Res."},{"key":"2024102405354680900_B47","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/0197-4580(95)00025-A","article-title":"Tau domains, phosphorylation, and interactions with microtubules","volume":"16","author":"Mandelkow","year":"1995","journal-title":"Neurobiol. Aging"},{"key":"2024102405354680900_B48","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/s13578-016-0124-4","article-title":"Function and regulation of tau conformations in the development and treatment of traumatic brain injury and neurodegeneration","volume":"6","author":"Albayram","year":"2016","journal-title":"Cell Biosci."}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/138\/21\/1329\/962581\/cs-2024-0616.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/138\/21\/1329\/962581\/cs-2024-0616.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T01:36:03Z","timestamp":1729733763000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/138\/21\/1329\/235023\/Complex-regulation-of-tau-phosphorylation-by-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,24]]},"references-count":48,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2024,11,6]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20240616","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,11]]},"published":{"date-parts":[[2024,10,24]]}}}