抑制血管生成素-2通过减少周细胞损失来拯救散发性脑动静脉畸形

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Angiogenesis Pub Date : 2024-12-05 DOI:10.1007/s10456-024-09957-1
Tianqi Tu, Shikun Zhang, Jingwei Li, Chendan Jiang, Jian Ren, Shiju Zhang, Xiaosheng Meng, Hao Peng, Dong Xing, Hongqi Zhang, Tao Hong, Jiaxing Yu
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引用次数: 0

摘要

脑动静脉畸形(bAVMs)是儿童和年轻人出血性中风的主要原因。这些病变被认为是由脑内皮细胞(bECs)的体细胞KRAS/BRAF突变引起的。在这项研究中,我们通过使用slc101c1 (BAC)-CreER驱动系诱导脑内皮特异性BrafV600E突变,引入了一种新的bAVM模型。该模型的病理特征与人类脑脊髓瘤相似,包括血管扩张和高渗透性,以及实质出血。我们观察到这些病变表现出典型的周细胞覆盖减少和周细胞-内皮细胞连接破坏。此外,我们发现在bAVM病变的内皮中ANGPT2水平显著升高,这可能是畸形血管周细胞缺陷的关键因素。ANGPT2中和抗体治疗证实阻断ANGPT2可恢复bAVM病变周细胞密度,提高微血管周围周细胞覆盖率,增强内皮细胞相关紧密连接蛋白覆盖率,使内皮屏障功能正常化。综上所述,我们的研究结果表明,BrafV600E突变的内皮细胞中ANGPT2表达增加是导致bavm周细胞缺陷的关键因素,这突出了抗ANGPT2治疗bavm的潜在有效性。
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Inhibition of Angiopoietin-2 rescues sporadic brain arteriovenous malformations by reducing pericyte loss

Brain arteriovenous malformations (bAVMs) are a major cause of hemorrhagic stroke in children and young adults. These lesions are thought to result from somatic KRAS/BRAF mutations in brain endothelial cells (bECs). In this study, we introduce a new bAVM model by inducing a brain endothelial-specific BrafV600E mutation using the Slc1o1c1(BAC)-CreER driver line. The pathological characteristics of this model resemble human bAVMs, including dilated and hyperpermeable vessels, as well as parenchymal hemorrhage. We observed that these lesions showed a typical reduction in pericyte coverage and disruption of the pericyte-endothelial cell connection. Additionally, we found that ANGPT2 levels were significantly increased in the endothelium of bAVM lesions, which may be a critical factor in the pericyte deficits of the malformed vessels. Treatment with an ANGPT2 neutralizing antibody confirmed that blocking ANGPT2 can restore pericyte density in bAVM lesions, improve pericyte coverage around microvessels, enhance tight junction protein coverage related to endothelial cells, and normalize endothelial barrier function. In summary, our findings suggest that increased ANGPT2 expression in endothelial cells with the BrafV600E mutation is a key factor in pericyte deficiencies in bAVMs, highlighting the potential effectiveness of anti-ANGPT2 therapy in treating bAVMs.

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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.
期刊最新文献
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