PMID- 36759189
OWN - NLM
STAT- MEDLINE
DCOM- 20230228
LR  - 20230922
IS  - 2373-2822 (Electronic)
IS  - 2373-2822 (Linking)
VI  - 10
IP  - 2
DP  - 2023 Feb
TI  - Neurovascular Development in Pten and Tsc2 Mouse Mutants.
LID - ENEURO.0340-22.2023 [pii]
LID - 10.1523/ENEURO.0340-22.2023 [doi]
AB  - Hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway 
      is linked to more than a dozen neurologic diseases, causing a range of 
      pathologies, including excess neuronal growth, disrupted neuronal migration, 
      cortical dysplasia, epilepsy and autism. The mTOR pathway also regulates 
      angiogenesis. For the present study, therefore, we queried whether loss of Pten 
      or Tsc2, both mTOR negative regulators, alters brain vasculature in three mouse 
      models: one with Pten loss restricted to hippocampal dentate granule cells 
      [DGC-Pten knock-outs (KOs)], a second with widespread Pten loss from excitatory 
      forebrain neurons (FB-Pten KOs) and a third with focal loss of Tsc2 from cortical 
      excitatory neurons (f-Tsc2 KOs). Total hippocampal vessel length and volume per 
      dentate gyrus were dramatically increased in DGC-Pten knock-outs. DGC-Pten 
      knock-outs had larger dentate gyri overall, however, and when normalized to these 
      larger structures, vessel density was preserved. In addition, tests of 
      blood-brain barrier integrity did not reveal increased permeability. FB-Pten KOs 
      recapitulated the findings in the more restricted DGC-Pten KOs, with increased 
      vessel area, but preserved vessel density. FB-Pten KOs did, however, exhibit 
      elevated levels of the angiogenic factor VegfA. In contrast to findings with 
      Pten, focal loss of Tsc2 from cortical excitatory neurons produced a localized 
      increase in vessel density. Together, these studies demonstrate that 
      hypervascularization is not a consistent feature of mTOR hyperactivation models 
      and suggest that loss of different mTOR pathway regulatory genes exert distinct 
      effects on angiogenesis.
CI  - Copyright (c) 2023 Dusing et al.
FAU - Dusing, Mary
AU  - Dusing M
AD  - Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 
      Cincinnati, OH 45229.
FAU - LaSarge, Candi L
AU  - LaSarge CL
AD  - Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 
      Cincinnati, OH 45229.
AD  - Departments of Anesthesia and Pediatrics, University of Cincinnati, Cincinnati, 
      OH 45229.
AD  - Center for Pediatric Neuroscience, Cincinnati Children's Hospital, Cincinnati, OH 
      45229.
AD  - Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH 45219.
FAU - White, Angela
AU  - White A
AD  - Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, 
      OH 45229.
FAU - Jerow, Lilian G
AU  - Jerow LG
AD  - Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH 45219.
FAU - Gross, Christina
AU  - Gross C
AUID- ORCID: 0000-0001-6057-2527
AD  - Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, 
      OH 45229.
AD  - Departments of Anesthesia and Pediatrics, University of Cincinnati, Cincinnati, 
      OH 45229.
AD  - Center for Pediatric Neuroscience, Cincinnati Children's Hospital, Cincinnati, OH 
      45229.
AD  - Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH 45219.
FAU - Danzer, Steve C
AU  - Danzer SC
AUID- ORCID: 0000-0003-4405-2999
AD  - Department of Anesthesia, Cincinnati Children's Hospital Medical Center, 
      Cincinnati, OH 45229 steve.danzer@cchmc.org.
AD  - Departments of Anesthesia and Pediatrics, University of Cincinnati, Cincinnati, 
      OH 45229.
AD  - Center for Pediatric Neuroscience, Cincinnati Children's Hospital, Cincinnati, OH 
      45229.
AD  - Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH 45219.
LA  - eng
GR  - R01 NS121042/NS/NINDS NIH HHS/United States
GR  - R21 HD093033/HD/NICHD NIH HHS/United States
GR  - R01 NS062806/NS/NINDS NIH HHS/United States
GR  - F32 NS083239/NS/NINDS NIH HHS/United States
GR  - R01 NS065020/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230223
PL  - United States
TA  - eNeuro
JT  - eNeuro
JID - 101647362
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - W36ZG6FT64 (Sirolimus)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - 0 (Tsc2 protein, mouse)
SB  - IM
CIN - eNeuro. 2023 Jul 21;10(7):. PMID: 37479502
MH  - Animals
MH  - Mice
MH  - *Epilepsy/genetics
MH  - Neurons/metabolism
MH  - Prosencephalon/metabolism
MH  - PTEN Phosphohydrolase/genetics/metabolism
MH  - Signal Transduction
MH  - Sirolimus
MH  - *TOR Serine-Threonine Kinases/metabolism
PMC - PMC9953070
OTO - NOTNLM
OT  - Vegf
OT  - angiogenesis
OT  - focal cortical dysplasia
OT  - mTOR
OT  - mtoropathy
OT  - tuberous sclerosis
COIS- The authors declare no competing financial interests.
EDAT- 2023/02/10 06:00
MHDA- 2023/03/03 06:00
PMCR- 2023/02/22
CRDT- 2023/02/09 21:41
PHST- 2022/08/22 00:00 [received]
PHST- 2023/02/01 00:00 [revised]
PHST- 2023/02/03 00:00 [accepted]
PHST- 2023/02/10 06:00 [pubmed]
PHST- 2023/03/03 06:00 [medline]
PHST- 2023/02/09 21:41 [entrez]
PHST- 2023/02/22 00:00 [pmc-release]
AID - ENEURO.0340-22.2023 [pii]
AID - eN-NWR-0340-22 [pii]
AID - 10.1523/ENEURO.0340-22.2023 [doi]
PST - epublish
SO  - eNeuro. 2023 Feb 23;10(2):ENEURO.0340-22.2023. doi: 10.1523/ENEURO.0340-22.2023. 
      Print 2023 Feb.