{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T13:53:40Z","timestamp":1791986020881,"version":"4.4.0"},"reference-count":37,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T00:00:00Z","timestamp":1713312000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010400","name":"Children's Mercy Hospital","doi-asserted-by":"publisher","award":["41595000"],"award-info":[{"award-number":["41595000"]}],"id":[{"id":"10.13039\/100010400","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":[[2024,5]]},"abstract":"\n Abstract<\/jats:title>\n \n The mechanisms governing brain vascularization during development remain poorly understood. A key regulator of developmental vascularization is delta like 4 (DLL4), a Notch ligand prominently expressed in endothelial cells (EC). Exposure to hyperoxia in premature infants can disrupt the development and functions of cerebral blood vessels and lead to long\u2010term cognitive impairment. However, its role in cerebral vascular development and the impact of postnatal hyperoxia on DLL4 expression in mouse brain EC have not been explored. We determined the DLL4 expression pattern and its downstream signalling gene expression in brain EC using\n \n Dll4\n +\/+<\/jats:sup>\n <\/jats:italic>\n and\n \n Dll4\n +\/LacZ<\/jats:sup>\n <\/jats:italic>\n mice. We also performed\n in vitro<\/jats:italic>\n studies using human brain microvascular endothelial cells. Finally, we determined\n Dll4<\/jats:italic>\n and\n Cldn5<\/jats:italic>\n expression in mouse brain EC exposed to postnatal hyperoxia. DLL4 is expressed in various cell types, with EC being the predominant one in immature brains. Moreover, DLL4 deficiency leads to persistent abnormalities in brain microvasculature and increased vascular permeability both\n in vivo<\/jats:italic>\n and\n in vitro<\/jats:italic>\n . We have identified that DLL4 insufficiency compromises endothelial integrity through the NOTCH\u2010NICD\u2010RBPJ\u2010CLDN5 pathway, resulting in the downregulation of the tight junction protein claudin 5 (CLDN5). Finally, exposure to neonatal hyperoxia reduces DLL4 and CLDN5 expression in developing mouse brain EC. We reveal that DLL4 is indispensable for brain vascular development and maintaining the blood\u2013brain barrier's function and is repressed by neonatal hyperoxia. We speculate that reduced DLL4 signalling in brain EC may contribute to the impaired brain development observed in neonates exposed to hyperoxia.\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 The role of delta like 4 (DLL4), a Notch ligand in vascular endothelial cells, in brain vascular development and functions remains unknown.<\/jats:p>\n <\/jats:list-item>\n \n \n We demonstrate that DLL4 is expressed at a high level during postnatal brain development in immature brains and DLL4 insufficiency leads to abnormal cerebral vasculature and increases vascular permeability both\n in vivo<\/jats:italic>\n and\n in vitro<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:list-item>\n \n We identify that DLL4\u00a0 regulates endothelial integrity through NOTCH\u2010NICD\u2010RBPJ\u2010CLDN5 signalling.<\/jats:p>\n <\/jats:list-item>\n \n \n Dll4<\/jats:italic>\n and\n Cldn5<\/jats:italic>\n expression are decreased in mouse brain endothelial cells exposed to postnatal hyperoxia.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp285716","type":"journal-article","created":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T01:33:46Z","timestamp":1713404026000},"page":"2265-2285","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Delta like 4 regulates cerebrovascular development and endothelial integrity via DLL4\u2010NOTCH\u2010CLDN5 pathway and is vulnerable to neonatal hyperoxia"],"prefix":"10.1113","volume":"602","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7763-1052","authenticated-orcid":false,"given":"Xingrao","family":"Ke","sequence":"first","affiliation":[{"name":"Department of Pediatrics Division of Neonatology Children's Mercy Kansas City MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Division of Neonatology Children's Mercy Kansas City MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Division of Neonatology Children's Mercy Kansas City MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7226-6479","authenticated-orcid":false,"given":"Sherry","family":"Mabry","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Division of Neonatology Children's Mercy Kansas City MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Division of Neonatology Children's Mercy Kansas City MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather L.","family":"Menden","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Division of Neonatology Children's Mercy Kansas City MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkatesh","family":"Sampath","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Division of Neonatology Children's Mercy Kansas City MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"Lane","sequence":"additional","affiliation":[{"name":"Department of Administration, Children Mercy Research Institute Children's Mercy Kansas City MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,4,17]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00095.2018"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.164.10.2101140"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00610.2018"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.211912.112"},{"key":"e_1_2_5_6_1","doi-asserted-by":"crossref","unstructured":"Cipolla M. 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