Somatic BrafV600E mutation in the cerebral endothelium induces brain arteriovenous malformations

• DOI: 10.1007/s10456-024-09918-8
• Publication Date: 2024-05-03T14:37:57Z
• Authors: Tianqi Tu; Jiaxing Yu; Chendan Jiang; Shikun Zhang; Jingwei Li; Jian Ren; Shiju Zhang; Yuan Zhou; Ziwei Cui; Haohan Lu; Xiaosheng Meng; Zhanjing Wang; Dong Xing; Hongqi Zhang; Tao Hong
• Keywords: Intracranial Arteriovenous Malformations; Proto-Oncogene Proteins B-raf; Mice, Inbred C57BL; Mice; Disease Models, Animal; Mutation; Oximes; Imidazoles; Animals; Humans; Brain; Mice, Transgenic; Endothelium, Vascular

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.