Biology of vascular malformations of the brain.
Biology of vascular malformations of the brain.
复制标题
大脑血管畸形的生物学。
DOI：
10.1161/strokeaha.109.563692
复制
发表时间：
2009-12
期刊：
影响因子：
8.3
通讯作者：
Biology of Vascular Malformations of the Brain NINDS Workshop Collaborators
中科院分区：
文献类型：
--
作者：
Leblanc GG;Golanov E;Awad IA;Young WL;Biology of Vascular Malformations of the Brain NINDS Workshop Collaborators
本文就脑血管畸形（VMBs）的遗传、分子、细胞和发育机制的研究进展进行综述，包括脑海绵状血管畸形（CCM）、散发性脑动静脉畸形（AVM）和遗传性出血性毛细血管扩张症（HHT）的AVM。与CCM、HHT和散发性AVM相关的基因突变和遗传风险因素的鉴定使这些疾病的动物模型的开发成为可能，并为其病因学提供了新的见解。迄今为止，所有与VMB相关的基因在血管生成和血管重塑中具有已知或可能的作用。最近的工作表明，血管生成过程中最严重的破坏VMB基因突变是血管稳定，血管内皮细胞形成毛细血管，加强其细胞间连接，并招募平滑肌细胞的血管壁的过程。此外，现在有很好的证据表明，在某些情况下，CCM病变的形成涉及一个遗传的两次打击机制，其中CCM基因的一个拷贝中的生殖系突变，随后是另一个拷贝中的体细胞突变。也有越来越多的证据表明，当VMB基因的单个等位基因发生突变时，环境的二次打击会产生病变。最近的发现开始解释了当受到其他不利的遗传或环境因素的挑战时，VMB基因的突变如何使血管容易破裂，并提出了候选治疗方法。对人类VMB形成和进展的细胞机制的理解落后于动物模型。病变生物学的新知识将刺激新的转化工作。一些完善的临床和遗传数据库工作已经到位，进一步的进展将通过这些合作的扩展和标准化来促进。
This review discusses recent research on the genetic, molecular, cellular, and developmental mechanisms underlying the etiology of vascular malformations of the brain (VMBs), including cerebral cavernous malformation (CCM), sporadic brain arteriovenous malformation (AVM), and the AVMs of hereditary hemorrhagic telangiectasia (HHT). The identification of gene mutations and genetic risk factors associated with CCM, HHT, and sporadic AVM has enabled the development of animal models for these diseases and provided new insights into their etiology. All of the genes associated with VMBs to date have known or plausible roles in angiogenesis and vascular remodeling. Recent work suggests that the angiogenic process most severely disrupted by VMB gene mutation is that of vascular stabilization, the process whereby vascular endothelial cells form capillary tubes, strengthen their intercellular junctions, and recruit smooth muscle cells to the vessel wall. In addition, there is now good evidence that in some cases CCM lesion formation involves a genetic two-hit mechanism, in which a germline mutation in one copy of a CCM gene is followed by a somatic mutation in the other copy. There is also increasing evidence that environmental second hits can produce lesions when there is a mutation to a single allele of a VMB gene. Recent findings begin to explain how mutations in VMB genes render vessels vulnerable to rupture when challenged with other inauspicious genetic or environmental factors, and have suggested candidate therapeutics. Understanding of the cellular mechanisms of VMB formation and progression in humans has lagged behind that in animal models. New knowledge of lesion biology will spur new translational work. Several well-established clinical and genetic database efforts are already in place, and further progress will be facilitated by collaborative expansion and standardization of these.