Authors :
First Author: Dongjun Guo, MD, PhD – Washington University School of Medicine
Presenting Author: Michael Wong, MD, Phd – Washington University School of Medicine
Bo Zhang, MD, PhD – Washington University School of Medicine; Lirong Han, BS – Washington University School of Medicine; Nicholas Rensing, BS – Washington University School of Medicine; Michael Wong, MD, PhD – Washington University School of Medicine
Rationale:
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. We investigated abnormalities in brain VEGF expression, cerebral blood vessel anatomy, and blood-brain barrier (BBB) structure and function and the potential role of these abnormalities in epileptogenesis in a mouse model of TSC. Methods:
Tsc1GFAPCKO 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, or BBB modulators were assessed in some of these assays, as well as on seizures by video-EEG. Results:
VEGF expression was elevated in cortex of Tsc1GFAPCKO mice, which was reversed by the mTOR inhibitor, rapamycin. Tsc1GFAPCKO 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 Tsc1GFAPCKO mice, also in an apatinib-dependent manner. A BBB modulator (RepSox), but not the VEGF antagonist, decreased seizures in Tsc1GFAPCKO mice.Conclusions:
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 in TSC, but functional consequences of these vascular abnormalities require further investigation.Funding:
Department of Defense Tuberous Sclerosis Complex Research Program W81XWH2110286; National Institutes of Health R01NS056872