ANG2 Blockade Diminishes Proangiogenic Cerebrovascular Defects Associated With Models of Hereditary Hemorrhagic Telangiectasia.
ANG2 Blockade Diminishes Proangiogenic Cerebrovascular Defects Associated With Models of Hereditary Hemorrhagic Telangiectasia.
复制标题
ANG2阻断可减少与遗传性出血性毛细血管扩张模型相关的促血管生成性脑血管缺陷。
DOI：
10.1161/atvbaha.123.319385
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Meadows,StryderM
中科院分区：
文献类型：
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作者：
Zhou,Xingyan;Pucel,JennaC;Nomura-Kitabayashi,Aya;Chandakkar,Pallavi;Guidroz,AdellaP;Jhangiani,NikitaL;Bao,Duran;Fan,Jia;Arthur,HelenM;Ullmer,Christoph;Klein,Christian;Marambaud,Philippe;Meadows,StryderM
遗传性出血性毛细血管扩张症（HHT）是一种以动静脉畸形和血管扩张为特征的血管疾病。然而，没有有效的药物治疗来对抗HHT患者的动静脉畸形形成。在这里，我们的目的是解决是否血管生成素-2（ANG 2）在内皮细胞水平升高是一个保守的功能，在小鼠模型的3种主要形式的HHT，可以被中和，以治疗脑动静脉畸形和相关的血管缺陷。此外，我们试图确定与HHT.METHODSCerebrovascular缺陷，包括动静脉畸形和血管口径增加，其特征在于在小鼠模型的3种常见形式的HHT使用transcriptomic和染料注射labeling methods. CRYSTSComparative RNA测序分析分离的脑内皮细胞揭示了一个共同的，但独特的proangiogenic转录程序与HHT。这包括与对照组相比，HHT小鼠脑血管ANG 2表达的一致上调及其受体Tyr激酶与IG和EGF同源结构域（TIE 2/TEK）的下调。此外，体外实验显示TEK信号传导活性在HHT环境中受到阻碍。ANG 2的药理学阻断改善了所有HHT模型中的脑血管病理，尽管程度不同。转录组学分析进一步表明，ANG 2抑制正常化的脑血管通过影响一个子集的基因参与血管生成和细胞迁移processes.CONCLUSIONSElevation的ANG 2在脑血管是一个共同的特点之间的小鼠模型的常见形式的HHT。抑制ANG 2活性可显著限制或预防HHT小鼠脑动静脉畸形形成和血管扩张。因此，ANG 2靶向治疗可能是治疗与所有形式HHT相关的动静脉畸形和血管病变的一种令人信服的方法。
BACKGROUNDHereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by arteriovenous malformations and blood vessel enlargements. However, there are no effective drug therapies to combat arteriovenous malformation formation in patients with HHT. Here, we aimed to address whether elevated levels of ANG2 (angiopoietin-2) in the endothelium is a conserved feature in mouse models of the 3 major forms of HHT that could be neutralized to treat brain arteriovenous malformations and associated vascular defects. In addition, we sought to identify the angiogenic molecular signature linked to HHT.METHODSCerebrovascular defects, including arteriovenous malformations and increased vessel calibers, were characterized in mouse models of the 3 common forms of HHT using transcriptomic and dye injection labeling methods.RESULTSComparative RNA sequencing analyses of isolated brain endothelial cells revealed a common, but unique proangiogenic transcriptional program associated with HHT. This included a consistent upregulation in cerebrovascular expression of ANG2 and downregulation of its receptor Tyr kinase with Ig and EGF homology domains (TIE2/TEK) in HHT mice compared with controls. Furthermore, in vitro experiments revealed TEK signaling activity was hampered in an HHT setting. Pharmacological blockade of ANG2 improved brain vascular pathologies in all HHT models, albeit to varying degrees. Transcriptomic profiling further indicated that ANG2 inhibition normalized the brain vasculature by impacting a subset of genes involved in angiogenesis and cell migration processes.CONCLUSIONSElevation of ANG2 in the brain vasculature is a shared trait among the mouse models of the common forms of HHT. Inhibition of ANG2 activity can significantly limit or prevent brain arteriovenous malformation formation and blood vessel enlargement in HHT mice. Thus, ANG2-targeted therapies may represent a compelling approach to treat arteriovenous malformations and vascular pathologies related to all forms of HHT.