PMID- 31125447
OWN - NLM
STAT- MEDLINE
DCOM- 20200410
LR  - 20211204
IS  - 1528-1167 (Electronic)
IS  - 0013-9580 (Print)
IS  - 0013-9580 (Linking)
VI  - 60
IP  - 6
DP  - 2019 Jun
TI  - Hypervascularization in mTOR-dependent focal and global cortical malformations 
      displays differential rapamycin sensitivity.
PG  - 1255-1265
LID - 10.1111/epi.15969 [doi]
AB  - OBJECTIVES: Patients with mammalian target of rapamycin (mTOR)-dependent 
      malformations of cortical development (MCDs) 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 MCD with and without seizures, and whether it is 
      sensitive to the mTOR blocker, rapamycin, that is approved for epilepsy treatment 
      in tuberous sclerosis complex. METHODS: We used two experimental models of 
      mTOR-dependent MCD consisting of conditional transgenic mice containing 
      Tsc1(null) cells in the forebrain generating a global malformation associated 
      with seizures and of wild-type mice containing a focal malformation in the 
      somatosensory cortex generated by in utero electroporation (IUE) that does not 
      lead to seizures. Alterations in blood vessels and the effects of a 2-week-long 
      rapamycin treatment on these phenotypes were assessed in juvenile mice. RESULTS: 
      Blood vessels in both the focal and global MCDs 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 mg/kg, every 2 days) partially rescued vessel abnormalities in the focal MCD 
      model, but it did not ameliorate the vessel abnormalities in the global MCD model 
      that required higher rapamycin dosage for a partial rescue. SIGNIFICANCE: Here, 
      we identified hypervascularization in mTOR-dependent MCD 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 MCD 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 MCD suggest that rapamycin treatment will need to be titrated to match 
      the type of MCD.
CI  - Wiley Periodicals, Inc. (c) 2019 International League Against Epilepsy.
FAU - Zhang, Longbo
AU  - Zhang L
AD  - Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 
      China.
AD  - Departments of Neurosurgery and Cellular & Molecular Physiology, Yale University 
      School of Medicine, New Haven, Connecticut.
FAU - Huang, Tianxiang
AU  - Huang T
AD  - Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 
      China.
AD  - Departments of Neurosurgery and Cellular & Molecular Physiology, Yale University 
      School of Medicine, New Haven, Connecticut.
FAU - Teaw, Shannon
AU  - Teaw S
AD  - Departments of Neurosurgery and Cellular & Molecular Physiology, Yale University 
      School of Medicine, New Haven, Connecticut.
FAU - Bordey, Angelique
AU  - Bordey A
AUID- ORCID: 0000-0003-3496-3385
AD  - Departments of Neurosurgery and Cellular & Molecular Physiology, Yale University 
      School of Medicine, New Haven, Connecticut.
LA  - eng
GR  - The Swebilius Foundation/International
GR  - R21 NS093510/NS/NINDS NIH HHS/United States
GR  - (R21 NS093510/NIH/NINDS/International
GR  - TS150058/DoD/International
GR  - R01 NS111980/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20190524
PL  - United States
TA  - Epilepsia
JT  - Epilepsia
JID - 2983306R
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Blood Vessels/pathology
MH  - Cell Size
MH  - Dendrites/pathology
MH  - Electroporation
MH  - Female
MH  - Malformations of Cortical Development/*metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Neovascularization, Pathologic/pathology
MH  - Neurons/pathology
MH  - Plasmids/genetics
MH  - Pregnancy
MH  - Seizures/drug therapy/etiology/pathology
MH  - Sirolimus/*pharmacology
MH  - Somatosensory Cortex/pathology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/*metabolism
MH  - Tuberous Sclerosis/complications/drug therapy
PMC - PMC6558978
MID - NIHMS1026647
OTO - NOTNLM
OT  - mTOR
OT  - epilepsy
OT  - focal cortical dysplasia
OT  - hyperperfusion
OT  - hypervascularization
OT  - microvessel
OT  - rapamycin
OT  - tuber
OT  - tuberous sclerosis complex
OT  - vessel
COIS- Disclosure: None of the authors has any conflict of interest to disclose. We 
      confirm that we have read the Journal's position on issues involved in ethical 
      publication and affirm that this report is consistent with those guidelines.
EDAT- 2019/05/28 06:00
MHDA- 2020/04/11 06:00
PMCR- 2020/06/01
CRDT- 2019/05/25 06:00
PHST- 2018/11/21 00:00 [received]
PHST- 2019/04/26 00:00 [revised]
PHST- 2019/04/26 00:00 [accepted]
PHST- 2019/05/28 06:00 [pubmed]
PHST- 2020/04/11 06:00 [medline]
PHST- 2019/05/25 06:00 [entrez]
PHST- 2020/06/01 00:00 [pmc-release]
AID - 10.1111/epi.15969 [doi]
PST - ppublish
SO  - Epilepsia. 2019 Jun;60(6):1255-1265. doi: 10.1111/epi.15969. Epub 2019 May 24.