{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:48:49Z","timestamp":1790765329513,"version":"4.1.0"},"reference-count":35,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Ministry of Economy and Competitiveness, co-financed by the Carlos III Health Institute (ISCIII) and European Regional Development Fund (FEDER).","award":["PI16\/00493 and PI19\/01096"],"award-info":[{"award-number":["PI16\/00493 and PI19\/01096"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Aquaporin-4 (AQP4) is the principal water channel in the brain being expressed in astrocytes and ependymal cells. AQP4 plays an important role in cerebrospinal fluid (CSF) homeostasis, and alterations in its expression have been associated with hydrocephalus. AQP4 contributes to the development of hydrocephalus by hypoxia in aged mice, reproducing such principal characteristics of the disease. Here, we explore whether these alterations associated with the hydrocephalic state are permanent or can be reverted by reexposure to normoxia. Alterations such as ventriculomegaly, elevated intracranial pressure, and cognitive deficits were reversed, whereas deficits in CSF outflow and ventricular distensibility were not recovered, remaining impaired even one month after reestablishment of normoxia. Interestingly, in AQP4\u2212\/\u2212 mice, the impairment in CSF drainage and ventricular distensibility was completely reverted by re-normoxia, indicating that AQP4 has a structural role in the chronification of those alterations. Finally, we show that aged mice subjected to two hypoxic episodes experience permanent ventriculomegaly. These data reveal that repetitive hypoxic events in aged cerebral tissue promote the permanent alterations involved in hydrocephalic pathophysiology, which are dependent on AQP4 expression.<\/jats:p>","DOI":"10.3390\/ijms22189745","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T12:20:37Z","timestamp":1631190037000},"page":"9745","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Aquaporin-4 Mediates Permanent Brain Alterations in a Mouse Model of Hypoxia-Aged Hydrocephalus"],"prefix":"10.3390","volume":"22","author":[{"given":"Jos\u00e9 Luis","family":"Trillo-Contreras","sequence":"first","affiliation":[{"name":"Institute of Biomedicine of Seville-IBiS, University Hospital Virgen del Roc\u00edo, CSIC, University of Seville, 41013 Seville, Spain"},{"name":"Department of Medical Physiology and Biophysics, University of Seville, 41009 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Jos\u00e9","family":"Toledo-Aral","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine of Seville-IBiS, University Hospital Virgen del Roc\u00edo, CSIC, University of Seville, 41013 Seville, Spain"},{"name":"Department of Medical Physiology and Biophysics, University of Seville, 41009 Seville, Spain"},{"name":"Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2131-9013","authenticated-orcid":false,"given":"Javier","family":"Villadiego","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine of Seville-IBiS, University Hospital Virgen del Roc\u00edo, CSIC, University of Seville, 41013 Seville, Spain"},{"name":"Department of Medical Physiology and Biophysics, University of Seville, 41009 Seville, Spain"},{"name":"Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4758-9428","authenticated-orcid":false,"given":"Miriam","family":"Echevarr\u00eda","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine of Seville-IBiS, University Hospital Virgen del Roc\u00edo, CSIC, University of Seville, 41013 Seville, Spain"},{"name":"Department of Medical Physiology and Biophysics, University of Seville, 41009 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1038\/nrn1252","article-title":"The molecular basis of water transport in the brain","volume":"4","author":"Ottersen","year":"2003","journal-title":"Nat. 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