MicroRNA‐137 and microRNA‐195 inhibit vasculogenesis in brain arteriovenous malformations

• Published in: Annals of neurology 2017-09, Vol.82 (3), p.371-384
• Main Authors: Huang, Jun, Song, Jianping, Qu, Meijie, Wang, Yang, An, Qingzhu, Song, Yaying, Yan, Wei, Wang, Bingshun, Wang, Xiaojin, Zhang, Song, Chen, Xi, Zhao, Bing, Liu, Peixi, Xu, Tongyi, Zhang, Zhijun, Greenberg, David A., Wang, Yongting, Gao, Pingjin, Zhu, Wei, Yang, Guo‐Yuan
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Adults; Arteriovenous Fistula - genetics; Arteriovenous Fistula - metabolism; Arteriovenous Fistula - pathology; Brain; Cell migration; Cell Movement - physiology; Cell proliferation; Cell Proliferation - physiology; Cholecystokinin; Cytometry; Female; Flow cytometry; Gene Expression Profiling; Hemangioblastoma - genetics; Hemangioblastoma - metabolism; Hemangioblastoma - pathology; Hemorrhage; Humans; Immunohistochemistry; In vivo methods and tests; Intracranial Arteriovenous Malformations - genetics; Intracranial Arteriovenous Malformations - metabolism; Intracranial Arteriovenous Malformations - pathology; Male; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; miRNA; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Pathogenesis; Protein expression; Proteins; Proteomics; Ribonucleic acid; RNA; Smooth muscle; Suppressors; Young Adult; Young adults
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.25015

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. Ann Neurol 2017;82:371–384