{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:34:54Z","timestamp":1790742894432,"version":"4.1.0"},"reference-count":47,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2020,5,24]],"date-time":"2020-05-24T00:00:00Z","timestamp":1590278400000},"content-version":"am","delay-in-days":366,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#am"},{"start":{"date-parts":[[2019,5,24]],"date-time":"2019-05-24T00:00:00Z","timestamp":1558656000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["TS150058"],"award-info":[{"award-number":["TS150058"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2019,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>Patients with <jats:styled-content style=\"fixed-case\">mammalian target of rapamycin (mTOR)<\/jats:styled-content>\u2013dependent malformations of cortical development (<jats:styled-content style=\"fixed-case\">MCD<\/jats:styled-content>s) associated with seizures display hyperperfusion and increased vessel density of the dysmorphic cortical tissue. Some studies have suggested that the vascular defect occurred independently of seizures. Here, we further examined whether hypervascularization occurs in animal models of global and focal <jats:styled-content style=\"fixed-case\">MCD<\/jats:styled-content> with and without seizures, and whether it is sensitive to the <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> blocker, rapamycin, that is approved for epilepsy treatment in tuberous sclerosis complex.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used two experimental models of <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content>\u2010dependent <jats:styled-content style=\"fixed-case\">MCD<\/jats:styled-content> consisting of conditional transgenic mice containing <jats:italic>Tsc1<\/jats:italic><jats:sup>null<\/jats:sup> cells in the forebrain generating a global malformation associated with seizures and of wild\u2010type mice containing a focal malformation in the somatosensory cortex generated by in utero electroporation (<jats:styled-content style=\"fixed-case\">IUE<\/jats:styled-content>) that does not lead to seizures. Alterations in blood vessels and the effects of a 2\u2010week\u2013long rapamycin treatment on these phenotypes were assessed in juvenile mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Blood vessels in both the focal and global <jats:styled-content style=\"fixed-case\">MCD<\/jats:styled-content>s of postnatal day 14 mice displayed significant increase in vessel density, branching index, total vessel length, and decreased tissue lacunarity. In addition, rapamycin treatment (0.5\u00a0mg\/kg, every 2\u00a0days) partially rescued vessel abnormalities in the focal <jats:styled-content style=\"fixed-case\">MCD<\/jats:styled-content> model, but it did not ameliorate the vessel abnormalities in the global <jats:styled-content style=\"fixed-case\">MCD<\/jats:styled-content> model that required higher rapamycin dosage for a partial rescue.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Here, we identified hypervascularization in <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content>\u2010dependent <jats:styled-content style=\"fixed-case\">MCD<\/jats:styled-content> in the absence of seizures in young mice, suggesting that increased angiogenesis occurs during development in parallel to alterations in corticogenesis. In addition, a predictive functional outcome is that dysplastic neurons forming <jats:styled-content style=\"fixed-case\">MCD<\/jats:styled-content> will have better access to oxygen and metabolic supplies via their closer proximity to blood vessels. Finally, the difference in rapamycin sensitivity between a focal and global <jats:styled-content style=\"fixed-case\">MCD<\/jats:styled-content> suggest that rapamycin treatment will need to be titrated to match the type of <jats:styled-content style=\"fixed-case\">MCD<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.15969","type":"journal-article","created":{"date-parts":[[2019,5,24]],"date-time":"2019-05-24T16:23:39Z","timestamp":1558715019000},"page":"1255-1265","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Hypervascularization in <scp>mTOR<\/scp>\u2010dependent focal and global cortical malformations displays differential rapamycin sensitivity"],"prefix":"10.1111","volume":"60","author":[{"given":"Longbo","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Xiangya Hospital Central South University Changsha China"},{"name":"Departments of Neurosurgery and Cellular &amp; Molecular Physiology Yale University School of Medicine New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianxiang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Xiangya Hospital Central South University Changsha China"},{"name":"Departments of Neurosurgery and Cellular &amp; Molecular Physiology Yale University School of Medicine New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"Teaw","sequence":"additional","affiliation":[{"name":"Departments of Neurosurgery and Cellular &amp; Molecular Physiology Yale University School of Medicine New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3496-3385","authenticated-orcid":false,"given":"Ang\u00e9lique","family":"Bordey","sequence":"additional","affiliation":[{"name":"Departments of Neurosurgery and Cellular &amp; Molecular Physiology Yale University School of Medicine New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,5,24]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.31887\/DCNS.2008.10.1\/rjleventer"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2007.01421.x"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1703784"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24368"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24126"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.191"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001594"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000118"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv045"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24444"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.01.030"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3824"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1177\/1550059417697841"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra055323"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2010.02777.x"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2012.00581.x"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2006.00847.x"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073813488666"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0029-1237721"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.2000.tb00327.x"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.42.s6.6.x"},{"key":"e_1_2_8_23_1","first-page":"105","article-title":"Epilepsy, cerebral blood flow, and cerebral metabolic rate","volume":"4","author":"Duncan R","year":"1992","journal-title":"Cerebrovasc Brain Metab Rev"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2010.11.031"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt018"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-008-0354-6"},{"key":"e_1_2_8_27_1","first-page":"5173","article-title":"Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin","volume":"63","author":"El\u2010Hashemite N","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31419-2"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11753"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2011.09.008"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.09.009"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI44909"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0038174"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M805822200"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1605740113"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0027385"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.08.024"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005637"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-15-06309.2002"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1840-12.2013"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.09.017"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2260-18.2019"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijdevneu.2013.02.008"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.182296499"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-3806(95)00177-8"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/1096-9861(20001002)425:4<479::AID-CNE2>3.0.CO;2-3"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2006.06.017"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijdevneu.2016.01.001"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fepi.15969","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.15969","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/epi.15969","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/am-pdf\/10.1111\/epi.15969","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.15969","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,10]],"date-time":"2023-09-10T09:12:44Z","timestamp":1694337164000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/epi.15969"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,24]]},"references-count":47,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2019,6]]}},"alternative-id":["10.1111\/epi.15969"],"URL":"https:\/\/doi.org\/10.1111\/epi.15969","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,24]]},"assertion":[{"value":"2018-11-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-04-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-05-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}