{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T05:20:40Z","timestamp":1788067240376,"version":"build-2784847793"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>The physiopathology of life-threatening cerebrovascular complications in preeclampsia is unknown. We investigated whether disruption of the blood-brain barrier, generated using circulating small extracellular vesicles (sEVs) from women with preeclampsia or placentae cultured under hypoxic conditions, impairs the expression of tight junction proteins, such as CLDN5 (claudin-5), mediated by VEGF (vascular endothelial growth factor), and activation of KDR (VEGFR2 [VEGF receptor 2]).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We perform a preclinical mechanistic study using sEVs isolated from plasma of pregnant women with normal pregnancy (sEVs-NP; n=9), sEVs isolated from plasma of women with preeclampsia (sEVs-PE; n=9), or sEVs isolated from placentas cultured in normoxia (sEVs-Nor; n=10) or sEVs isolated from placentas cultured in hypoxia (sEVs-Hyp; n=10). The integrity of the blood-brain barrier was evaluated using in vitro (human [hCMEC\/D3] and mouse [BEND\/3 (brain endothelial cell 3)] brain endothelial cell lines) and in vivo (nonpregnant C57BL\/6J mice [4\u20135 months old; n=13] injected with sEVs-Hyp) models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      sEVs-PE and sEVs-Hyp reduced total and membrane-associated protein CLDN5 levels (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.05). These results were negated with sEVs-PE sonication. sEVs-Hyp injected into nonpregnant mice generated neurological deficits and blood-brain barrier disruption, specifically in the posterior area of the brain, associated with brain endothelial cell uptake of sEVs, sEVs-Hyp high extravasation, and reduction in CLDN5 levels in the brain cortex. Furthermore, sEVs-PE and sEVs-sHyp had higher VEGF levels than sEVs-NP and sEVs-Nor. Human brain endothelial cells exposed to sEVs-PE exhibited a reduction in the activation of KDR. Reduction in CLDN5 observed in cells treated with sEVs-Hyp was further enhanced in cells treated with KDR selective inhibitor.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>sEVs-PE disrupts the blood-brain barrier, an effect replicated with sEVs-Hyp, and involves reduced CLDN5 and elevated VEGF contained within these vesicles. However, our results do not support the participation of KDR activation in the downregulation of CLDN5 observed with sEVs-Hyp. These findings will improve our understanding of the pathophysiology of cerebrovascular alterations in women with preeclampsia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.124.321077","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T05:00:26Z","timestamp":1733979626000},"page":"298-311","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["Extracellular Vesicles From Preeclampsia Disrupt the Blood-Brain Barrier by Reducing CLDN5"],"prefix":"10.1161","volume":"45","author":[{"given":"Hermes","family":"Sandoval","sequence":"first","affiliation":[{"name":"Vascular Physiology Laboratory, Department of Basic Sciences, Universidad del B\u00edo-B\u00edo, Chill\u00e1n, Chile (H.S., B.I., M.C., F.T., E.E.-G., J.A., C.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5449-460X","authenticated-orcid":true,"given":"Bel\u00e9n","family":"Ib\u00e1\u00f1ez","sequence":"additional","affiliation":[{"name":"Vascular Physiology Laboratory, Department of Basic Sciences, Universidad del B\u00edo-B\u00edo, Chill\u00e1n, Chile (H.S., B.I., M.C., F.T., E.E.-G., J.A., C.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mois\u00e9s","family":"Contreras","sequence":"additional","affiliation":[{"name":"Vascular Physiology Laboratory, Department of Basic Sciences, Universidad del B\u00edo-B\u00edo, Chill\u00e1n, Chile (H.S., B.I., M.C., F.T., E.E.-G., J.A., C.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Troncoso","sequence":"additional","affiliation":[{"name":"Vascular Physiology Laboratory, Department of Basic Sciences, Universidad del B\u00edo-B\u00edo, Chill\u00e1n, Chile (H.S., B.I., M.C., F.T., E.E.-G., J.A., C.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8828-1449","authenticated-orcid":true,"given":"Fidel O.","family":"Castro","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Faculty of Veterinary Sciences, Universidad de Concepci\u00f3n, Chillan, Chile (F.O.C., D.C., L.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2772-8793","authenticated-orcid":true,"given":"Diego","family":"Caama\u00f1o","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Faculty of Veterinary Sciences, Universidad de Concepci\u00f3n, Chillan, Chile (F.O.C., D.C., L.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1109-6936","authenticated-orcid":true,"given":"Lidice","family":"Mendez","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Faculty of Veterinary Sciences, Universidad de Concepci\u00f3n, Chillan, Chile (F.O.C., D.C., L.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5522-6705","authenticated-orcid":true,"given":"Estefanny","family":"Escudero-Guevara","sequence":"additional","affiliation":[{"name":"Vascular Physiology Laboratory, Department of Basic Sciences, Universidad del B\u00edo-B\u00edo, Chill\u00e1n, Chile (H.S., B.I., M.C., F.T., E.E.-G., J.A., C.E.)."},{"name":"PhD Program in Biomedical Sciences, Universidad de Talca, Chile (E.E.-G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7762-1417","authenticated-orcid":true,"given":"Francisco","family":"Nualart","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Celular, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Chile (F.N.)."},{"name":"Laboratory of Neurobiology and Stem Cells NeuroCellT, Department of Cellular Biology, Center for Advanced Microscopy CMA Bio-Bio, Faculty of Biological Sciences, University of Concepci\u00f3n, Chile (F.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2564-7348","authenticated-orcid":true,"given":"Hiten D.","family":"Mistry","sequence":"additional","affiliation":[{"name":"Division of Women and Children\u2019s Health, School of Life Course and Population Sciences, King\u2019s College London, United Kingdom (H.D.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7938-6994","authenticated-orcid":true,"given":"Lesia O.","family":"Kurlak","sequence":"additional","affiliation":[{"name":"Stroke Trials Unit, School of Medicine, Faculty of Medicine &amp; 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