MicroRNA-137 and MicroRNA-195*Inhibit Vasculogenesis in Brain Arteriovenous Malformations
MicroRNA-137 and MicroRNA-195*Inhibit Vasculogenesis in Brain Arteriovenous Malformations
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MicroRNA-137 和 microRNA-195 抑制脑动静脉畸形中的血管生成
DOI：
10.1002/ana.25015
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发表时间：
2017-09-01
影响因子：
11.2
通讯作者：
Yang, Guo-Yuan
中科院分区：
文献类型：
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作者：
Huang, Jun;Song, Jianping;Yang, Guo-Yuan
目的：脑动静脉畸形（AVM）是年轻人非创伤性脑出血的最常见原因。脑动静脉畸形的发生至今仍是个谜。我们研究microRNA（miRNA）的表达及其对脑AVM发病机制的贡献。方法：我们使用了大规模的miRNA分析16个样本，包括AVM，血管母细胞瘤，和控制，以确定一个独特的AVM miRNA签名。通过流式细胞术和免疫组化分离和鉴定AVM平滑肌细胞（AVMSMCs），然后在这些细胞中测试候选miRNAs。迁移，管形成，和CCK-8诱导的增殖试验用于测试的miRNA对AVMSMC的表型特性的影响。定量蛋白质组学方法被用来确定蛋白质表达的变化，在AVMSMCs处理的miRNA mimics.Results：一个独特的AVM的miRNA签名，包括大部分低表达的miRNA被确定。在这些miRNA中，miR-137和miR-195* 水平在AVM和组成性AVMSMC中显著降低。实验性地提高这些microRNA的水平抑制了体外AVMSMC的迁移、管形成和存活以及体内血管环的形成。蛋白质组学显示了AVMSMC的蛋白质表达特征，并鉴定了受miR-137和miR-195* 调控的下游蛋白质，这些蛋白质是参与血管发育的关键信号蛋白。我们的研究结果表明，miR-137和miR-195* 通过改变AVMSMC的表型特性，并且miR-137和miR-195* 表达的缺失会导致异常的血管发生。
Objective: Brain arteriovenous malformations (AVMs) are the most common cause of nontraumatic intracerebral hemorrhage in young adults. The genesis of brain AVM remains enigmatic. We investigated microRNA (miRNA) expression and its contribution to the pathogenesis of brain AVMs.Methods: We used a large-scale miRNA analysis of 16 samples including AVMs, hemangioblastoma, and controls to identify a distinct AVM miRNA signature. AVM smooth muscle cells (AVMSMCs) were isolated and identified by flow cytometry and immunohistochemistry, and candidate miRNAs were then tested in these cells. Migration, tube formation, and CCK-8-induced proliferation assays were used to test the effect of the miRNAs on phenotypic properties of AVMSMCs. A quantitative proteomics approach was used to identify protein expression changes in AVMSMCs treated with miRNA mimics.Results: A distinct AVM miRNA signature comprising a large portion of lowly expressed miRNAs was identified. Among these miRNAs, miR-137 and miR-195* levels were significantly decreased in AVMs and constituent AVMSMCs. Experimentally elevating the level of these microRNAs inhibited AVMSMC migration, tube formation, and survival in vitro and the formation of vascular rings in vivo. Proteomics showed the protein expression signature of AVMSMCs and identified downstream proteins regulated by miR-137 and miR-195* that were key signaling proteins involved in vessel development.Interpretation: Our results indicate that miR-137 and miR-195* act as vasculogenic suppressors in AVMs by altering phenotypic properties of AVMSMCs, and that the absence of miR-137 and miR-195* expression leads to abnormal vasculogenesis.