Abstract | OBJECTIVE: METHODS: Tsc1GFAP 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 vivo two-photon 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-electroencephalography. RESULTS:
VEGF expression was elevated in cortex of Tsc1GFAP CKO mice, which was reversed by the mTOR inhibitor rapamycin. Tsc1GFAP 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-related tight junction proteins occludin and claudin-5 were decreased in Tsc1GFAP CKO mice, also in an apatinib- and RepSox-dependent manner. The BBB stabilizer ( RepSox), but not the VEGF receptor antagonist ( apatinib), decreased seizures and improved survival in Tsc1GFAP CKO mice. SIGNIFICANCE: 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.
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Authors | Dongjun Guo, Bo Zhang, Lirong Han, Nicholas R Rensing, Michael Wong |
Journal | Epilepsia
(Epilepsia)
Vol. 65
Issue 2
Pg. 483-496
(Feb 2024)
ISSN: 1528-1167 [Electronic] United States |
PMID | 38049961
(Publication Type: Journal Article)
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Copyright | © 2023 International League Against Epilepsy. |
Chemical References |
- Vascular Endothelial Growth Factor A
- Tumor Suppressor Proteins
- Tuberous Sclerosis Complex 1 Protein
- TOR Serine-Threonine Kinases
- Sirolimus
- Receptors, Vascular Endothelial Growth Factor
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Topics |
- Humans
- Mice
- Animals
- Blood-Brain Barrier
- Vascular Endothelial Growth Factor A
(metabolism)
- Tuberous Sclerosis
(complications, genetics)
- Tumor Suppressor Proteins
(genetics)
- Tuberous Sclerosis Complex 1 Protein
(genetics, metabolism)
- Epilepsy
(genetics, metabolism)
- Seizures
- TOR Serine-Threonine Kinases
(genetics)
- Sirolimus
- Receptors, Vascular Endothelial Growth Factor
(metabolism)
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