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Nat Med:中大王敏教授等发表脑血管研究突破

摘要 : 2016年8月22日,国际学术权威刊物自然出版集团旗下子刊《Nature Medicine》杂志在线发表了中山大学附属第一医院王敏教授牵头和耶鲁大学血管研究中心吴殿青研究组合作完成的研究成果

 2016年8月22日,国际学术权威刊物自然出版集团旗下子刊《Nature Medicine》杂志在线发表了中山大学附属第一医院王敏教授牵头和耶鲁大学血管研究中心吴殿青研究组合作完成的研究成果“Endothelial exocytosis of angiopoietin-2 resulting from CCM3 deficiency contributes to cerebral cavernous malformation”。耶鲁大学血管研究中心周焕娇博士为论文第一作者,王敏教授和吴殿青研究员为论文共同通讯作者。

脑海绵状血管瘤(CCMs)是一种脑血管畸形,易导致癫痫、卒中发生。目前,CCMs的发病与进展机制不明,临床上通常采取内科治疗、手术治疗和放射介入治疗,缺乏精准靶向治疗。该研究针对CCMs发病机制,发现了CCM3(引起CCMs的三种突变基因之一)功能缺失可引起脑海绵状血管瘤的形成,血管生成素-2的分泌促进该疾病进展恶化,并通过动物模型证实血管生成素-2中和抗体能治愈脑海绵状血管畸形。研究成果提出了全新的CCMs发病机理,对阐明该病的发病机制、研究新靶点药物、实施精准靶向治疗提供了坚实的理论基础。

脑海绵状血管瘤动物模型中血管扩大(左图),血管生成素-2中和抗体能治愈脑海绵状血管畸形(右图)。小鼠脑组织切片用血管标记物CD31抗体(红色)和血管内皮细胞紧密连接蛋白Claudin-5抗体(绿色)共染,细胞核染色用DAPI标记(蓝色)。

原文链接:

Endothelial exocytosis of angiopoietin-2 resulting from CCM3 deficiency contributes to cerebral cavernous malformation

原文摘要:

Cerebral cavernous malformations (CCMs) are vascular malformations that affect the central nervous system and result in cerebral hemorrhage, seizure and stroke. CCMs arise from loss-of-function mutations in one of three genes: KRIT1 (also known as CCM1), CCM2 or PDCD10 (also known as CCM3). PDCD10 mutations in humans often result in a more severe form of the disease relative to mutations in the other two CCM genes, and PDCD10-knockout mice show severe defects, the mechanistic basis for which is unclear. We have recently reported that CCM3 regulates exocytosis mediated by the UNC13 family of exocytic regulatory proteins. Here, in investigating the role of endothelial cell exocytosis in CCM disease progression, we found that CCM3 suppresses UNC13B- and vesicle-associated membrane protein 3 (VAMP3)-dependent exocytosis of angiopoietin 2 (ANGPT2) in brain endothelial cells. CCM3 deficiency in endothelial cells augments the exocytosis and secretion of ANGPT2, which is associated with destabilized endothelial cell junctions, enlarged lumen formation and endothelial cell–pericyte dissociation. UNC13B deficiency, which blunts ANGPT2 secretion from endothelial cells, or treatment with an ANGPT2-neutralizing antibody normalizes the defects in the brain and retina caused by endothelial-cell-specific CCM3 deficiency, including the disruption of endothelial cell junctions, vessel dilation and pericyte dissociation. Thus, enhanced secretion of ANGPT2 in endothelial cells contributes to the progression of CCM disease, providing a new therapeutic approach for treating this devastating pathology.

来源: Nature Medicine 浏览次数:0

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