脑内皮中的体细胞BrafV600E突变会诱发脑动静脉畸形。

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE
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
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引用次数: 0

摘要

目前治疗脑动静脉畸形(BAVM)的方法存在相当大的风险,有时疗效不佳。因此,迫切需要一种与临床一致的脑动静脉畸形动物模型来研究其潜在的生物学机制并开发创新的治疗策略。值得注意的是,现有的小鼠模型由于 AVM 病变的异质性和非典型表型而实用性有限。在这里,我们建立了一种与人类临床表现一致的散发性脑动静脉畸形的新型小鼠模型。脑EC发生BrafV600E突变的小鼠发生的BAVM与人类病变非常相似。这种策略成功地诱导了不同年龄组和不同脑区的小鼠发生脑血管瘤。BAVM的病理特征主要是血管扩张,血管壁稳定性降低,伴有自发性出血和神经炎症。单细胞测序发现了与细胞骨架、细胞运动和细胞间连接有关的差异表达基因。研究发现,早期服用达拉非尼能有效延缓脑动静脉畸形的进展;然而,它对治疗已形成的脑动静脉畸形病灶的疗效仍不确定。总之,我们提出的方法成功地诱导出了与人类小鼠BAVM病变非常相似的BAVM,使该模型适用于研究BAVM的发病机制和评估潜在的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Somatic BrafV600E mutation in the cerebral endothelium induces brain arteriovenous malformations

Somatic BrafV600E mutation in the cerebral endothelium induces brain arteriovenous malformations

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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来源期刊
Angiogenesis
Angiogenesis PERIPHERAL VASCULAR DISEASE-
CiteScore
21.90
自引率
8.20%
发文量
37
审稿时长
6-12 weeks
期刊介绍: Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
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