{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T06:03:30Z","timestamp":1792476210724,"version":"4.5.0"},"reference-count":30,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,12,16]],"date-time":"2023-12-16T00:00:00Z","timestamp":1702684800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["TSCRP W81XWH2110286"],"award-info":[{"award-number":["TSCRP W81XWH2110286"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["P50 HD103525"],"award-info":[{"award-number":["P50 HD103525"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS056872"],"award-info":[{"award-number":["R01 NS056872"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["S10 RR027552"],"award-info":[{"award-number":["S10 RR027552"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Tuberous sclerosis complex (TSC) is a genetic disorder, characterized by tumor formation in the brain and other organs, and severe neurological symptoms, such as epilepsy. Abnormal vascular endothelial growth factor (VEGF) expression may promote angiogenesis in kidney and lung tumors in TSC and has been identified in brain specimens from TSC patients, but the role of VEGF and vascular abnormalities in neurological manifestations of TSC is poorly defined. In this study, we investigated abnormalities in brain VEGF expression, cerebral blood vessel anatomy, and blood\u2013brain barrier (BBB) structure and function in a mouse model of TSC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>Tsc1<\/jats:italic><jats:sup>GFAP<\/jats:sup>CKO mice were used to investigate VEGF expression and vascular abnormalities in the brain by Western blotting and immunohistochemical analysis of vascular and BBB markers. In\u00a0vivo two\u2010photon imaging was used to assess BBB permeability to normally impenetrable fluorescently labeled compounds. The effect of mechanistic target of rapamycin (mTOR) pathway inhibitors, VEGF receptor antagonists (apatinib), or BBB stabilizers (RepSox) was assessed in some of these assays, as well as on seizures by video\u2010electroencephalography.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>VEGF expression was elevated in cortex of <jats:italic>Tsc1<\/jats:italic><jats:sup>GFAP<\/jats:sup>CKO mice, which was reversed by the mTOR inhibitor rapamycin. <jats:italic>Tsc1<\/jats:italic><jats:sup>GFAP<\/jats:sup>CKO mice exhibited increased cerebral angiogenesis and vascular complexity in cortex and hippocampus, which were reversed by the VEGF receptor antagonist apatinib. BBB permeability was abnormally increased and BBB\u2010related tight junction proteins occludin and claudin\u20105 were decreased in <jats:italic>Tsc1<\/jats:italic><jats:sup>GFAP<\/jats:sup>CKO mice, also in an apatinib\u2010 and RepSox\u2010dependent manner. The BBB stabilizer (RepSox), but not the VEGF receptor antagonist (apatinib), decreased seizures and improved survival in <jats:italic>Tsc1<\/jats:italic><jats:sup>GFAP<\/jats:sup>CKO mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Increased brain VEGF expression is dependent on mTOR pathway activation and promotes cerebral vascular abnormalities and increased BBB permeability in a mouse model of TSC. BBB modulation may affect epileptogenesis and represent a rational treatment for epilepsy in TSC.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.17848","type":"journal-article","created":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T05:24:26Z","timestamp":1701753866000},"page":"483-496","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Cerebral vascular and blood brain\u2013barrier abnormalities in a mouse model of epilepsy and tuberous sclerosis complex"],"prefix":"10.1111","volume":"65","author":[{"given":"Dongjun","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Neurology and Hope Center for Neurological Disorders Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology and Hope Center for Neurological Disorders Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lirong","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Neurology and Hope Center for Neurological Disorders Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas R.","family":"Rensing","sequence":"additional","affiliation":[{"name":"Department of Neurology and Hope Center for Neurological Disorders Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3796-743X","authenticated-orcid":false,"given":"Michael","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Neurology and Hope Center for Neurological Disorders Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,12,16]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)61279-9"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.35"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(15)00069-1"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.01.021"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.4161\/org.6.2.11687"},{"issue":"6","key":"e_1_2_9_7_1","first-page":"445","article-title":"Serum VEGF\u2010D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the multicenter international Lymphangioleiomyomatosis efficacy of Sirolimus (MILES) trial the lancet","volume":"1","author":"Young L","year":"2013","journal-title":"Respir 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