Endothelial exocytosis of angiopoietin-2 resulting from CCM3 deficiency contributes to cerebral cavernous malformation.
Endothelial exocytosis of angiopoietin-2 resulting from CCM3 deficiency contributes to cerebral cavernous malformation.
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CCM3 缺陷引起的血管生成素 2 的内皮胞吐作用导致脑海绵状血管瘤
DOI：
10.1038/nm.4169
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发表时间：
2016-09
期刊：
影响因子：
82.9
通讯作者：
Min, Wang
中科院分区：
文献类型：
--
作者：
Zhou, Huanjiao Jenny;Qin, Lingfeng;Zhang, Haifeng;Tang, Wenwen;Ji, Weidong;He, Yun;Liang, Xiaoling;Wang, Zongren;Yuan, Qianying;Vortmeyer, Alexander;Toomre, Derek;Fuh, Germaine;Yan, Minghong;Kluger, Martin S.;Wu, Dianqing;Min, Wang
脑海绵状血管畸形（CCM）是影响中枢神经系统并导致脑出血、癫痫发作和中风的血管畸形。CCM由三种基因之一的功能丧失突变引起：CCM 1，CCM 2和CCM 3（PDCD 10）。人类中的CCM 3突变通常导致更严重形式的疾病，并且CCM 3敲除小鼠显示出严重的表型，其机制尚未确定。我们最近报道了CCM 3调节UNC 13家族介导的胞吐作用。在这里，我们研究内皮细胞（EC）胞吐在CCM疾病进展。我们发现CCM 3抑制脑内皮细胞中血管生成素-2（ANGPT 2）的UNC 13 B/VAMP 3依赖性胞吐。EC中的CCM 3消融增加了ANGPT 2的胞吐和分泌，与不稳定的EC连接、扩大的管腔形成和内皮细胞-周细胞解离相关。UNC 13 B缺陷使ANGPT 2从EC分泌减弱或ANGPT 2中和抗体使由CCM 3缺陷引起的缺陷正常化。更重要的是，ANGPT 2中和抗体治疗或UNC 13 B缺陷使CCM病变表型变钝，包括内皮细胞特异性CCM 3失活引起的脑和视网膜中EC连接破坏、血管扩张和周细胞解离。我们的研究表明，内皮细胞中ANGPT 2分泌的增强有助于CCM疾病的进展，为治疗这种破坏性病理提供了一种新的治疗方法。
Cerebral cavernous malformations (CCMs) are vascular malformations that affect the central nervous system and result in cerebral hemorrhage, seizure and stroke. CCM arises from loss-of-function mutations in one of three genes: CCM1, CCM2 and CCM3 (PDCD10). CCM3 mutations in human often result in a more severe form of the disease, and CCM3 knockout mice show severe phenotypes with yet-to-be defined mechanisms. We have recently reported that CCM3 regulates UNC13 family-mediated exocytosis. Here we investigate endothelial cells (EC) exocytosis in CCM disease progression. We find that CCM3 suppresses UNC13B/VAMP3-dependent exocytosis of angiopoietin-2 (ANGPT2) in brain endothelial cells. CCM3 ablation in EC augments exocytosis and secretion of ANGPT2, correlating with destabilized EC junctions, enlarged lumen formation, and endothelial cell-pericyte dissociations. UNC13B deficiency that blunts ANGPT2 secretion from EC or an ANGPT2 neutralization antibody normalizes the defects caused by CCM3 deficiency. More importantly, ANGPT2 neutralization antibody treatment or UNC13B deficiency blunts the CCM lesion phenotypes, including disruption of EC junctions, vessel dilation and pericyte dissociation, in the brains and retinas caused by endothelial cell-specific CCM3 inactivation. Our study reveals that enhanced secretion of ANGPT2 in endothelial cells contributes to the progression of the CCM disease, providing a novel therapeutic approach to treat this devastating pathology.
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DOI：
10.1161/atvbaha.112.300893
发表时间：
2013-03
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Kluger MS;Clark PR;Tellides G;Gerke V;Pober JS
通讯作者：
Pober JS
影响因子：
11.8
作者：
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通讯作者：
Yancopoulos, GD
影响因子：
20.1
作者：
Bruetsch, Rene;Liebler, Sven S.;Fischer, Andreas
通讯作者：
Fischer, Andreas
影响因子：
7.3
作者：
He Y;Zhang H;Yu L;Gunel M;Boggon TJ;Chen H;Min W
通讯作者：
Min W
DOI：
10.1186/cc7866
发表时间：
2009
期刊：
Critical care (London, England)
影响因子：
--
作者：
Kümpers P;van Meurs M;David S;Molema G;Bijzet J;Lukasz A;Biertz F;Haller H;Zijlstra JG
通讯作者：
Zijlstra JG