Abstract
Current treatments of brain arteriovenous malformation (BAVM) are associated with considerable risks and at times incomplete efficacy. Therefore, a clinically consistent animal model of BAVM is urgently needed to investigate its underlying biological mechanisms and develop innovative treatment strategies. Notably, existing mouse models have limited utility due to heterogenous and untypical phenotypes of AVM lesions. Here we developed a novel mouse model of sporadic BAVM that is consistent with clinical manifestations in humans. Mice with BrafV600E mutations in brain ECs developed BAVM closely resembled that of human lesions. This strategy successfully induced BAVMs in mice across different age groups and within various brain regions. Pathological features of BAVM were primarily dilated blood vessels with reduced vascular wall stability, accompanied by spontaneous hemorrhage and neuroinflammation. Single-cell sequencing revealed differentially expressed genes that were related to the cytoskeleton, cell motility, and intercellular junctions. Early administration of Dabrafenib was found to be effective in slowing the progression of BAVMs; however, its efficacy in treating established BAVM lesions remained uncertain. Taken together, our proposed approach successfully induced BAVM that closely resembled human BAVM lesions in mice, rendering the model suitable for investigating the pathogenesis of BAVM and assessing potential therapeutic strategies.
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Acknowledgements
We thank the lab members at Zhang and Hong lab and colleagues from China International Neuroscience Institute. This work is supported by the National Natural Science Foundation of China (No. 82220108010, 81971104, 82201439, 82122020, 82101369, 82102009 and 82330038). Beijing Municipal Commission of Education (BPHR20220113).
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This work is supported by the National Natural Science Foundation of China (No. 82220108010, 81971104, 82201439, 82122020, 82101369, 82102009 and 82330038). Beijing Municipal Commission of Education (BPHR20220113).
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TT, JY and TH conceptualized the study and designed experiments; TT, JY and CJ conducted the majority of experiments with help from JL, JR, YZ, ZC, HL, XM, and ZW; CJ and DX performed the bioinformatic analysis; all authors acquired data; TT and JY analysed the data; TT, JY and TH wrote the original draft of the manuscript; JY, HZ and TH secured funding; all authors edited and approved the manuscript.
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Tu, T., Yu, J., Jiang, C. et al. Somatic BrafV600E mutation in the cerebral endothelium induces brain arteriovenous malformations. Angiogenesis (2024). https://doi.org/10.1007/s10456-024-09918-8
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DOI: https://doi.org/10.1007/s10456-024-09918-8