Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX.
Department of Diagnostic and Interventional Imaging, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX.
Ann Neurol. 2021 May;89(5):926-941. doi: 10.1002/ana.26059. Epub 2021 Mar 22.
Brain arteriovenous malformations (bAVMs) are a leading cause of hemorrhagic stroke and neurological deficits in children and young adults, however, no pharmacological intervention is available to treat these patients. Although more than 95% of bAVMs are sporadic without family history, the pathogenesis of sporadic bAVMs is largely unknown, which may account for the lack of therapeutic options. KRAS mutations are frequently observed in cancer, and a recent unprecedented finding of these mutations in human sporadic bAVMs offers a new direction in the bAVM research. Using a novel adeno-associated virus targeting brain endothelium (AAV-BR1), the current study tested if endothelial KRAS mutation induces sporadic bAVMs in mice.
Five-week-old mice were systemically injected with either AAV-BR1-GFP or -KRAS . At 8 weeks after the AAV injection, bAVM formation and characteristics were addressed by histological and molecular analyses. The effect of MEK/ERK inhibition on KRAS -induced bAVMs was determined by treatment of trametinib, a US Food and Drug Administration (FDA)-approved MEK/ERK inhibitor.
The viral-mediated KRAS overexpression induced bAVMs, which were composed of a tangled nidus mirroring the distinctive morphology of human bAVMs. The bAVMs were accompanied by focal angiogenesis, intracerebral hemorrhages, altered vascular constituents, neuroinflammation, and impaired sensory/cognitive/motor functions. Finally, we confirmed that bAVM growth was inhibited by trametinib treatment.
Our innovative approach using AAV-BR1 confirms that KRAS mutations promote bAVM development via the MEK/ERK pathway, and provides a novel preclinical mouse model of bAVMs which will be useful to develop a therapeutic strategy for patients with bAVM. ANN NEUROL 2021;89:926-941.
脑动静脉畸形（bAVM）是儿童和青年出血性中风和神经功能缺损的主要原因，但目前尚无药物干预措施可用于治疗这些患者。尽管超过 95%的 bAVM 是无家族史的散发性，但散发性 bAVM 的发病机制在很大程度上尚不清楚，这可能是缺乏治疗选择的原因。KRAS 突变在癌症中经常观察到，最近在人类散发性 bAVM 中发现这些突变提供了 bAVM 研究的新方向。本研究使用一种新型针对脑内皮的腺相关病毒（AAV-BR1），检测内皮 KRAS 突变是否会在小鼠中诱导散发性 bAVM。
5 周龄的小鼠系统注射 AAV-BR1-GFP 或 -KRAS。在 AAV 注射 8 周后，通过组织学和分子分析来解决 bAVM 的形成和特征。通过用曲美替尼（一种美国食品和药物管理局（FDA）批准的 MEK/ERK 抑制剂）治疗来确定 MEK/ERK 抑制对 KRAS 诱导的 bAVM 的影响。
病毒介导的 KRAS 过表达诱导了 bAVM，其由一个纠结的中心组成，反映了人类 bAVM 的独特形态。bAVM 伴有局灶性血管生成、脑出血、血管成分改变、神经炎症和感觉/认知/运动功能受损。最后，我们证实 bAVM 的生长可以通过 trametinib 治疗来抑制。
我们使用 AAV-BR1 的创新方法证实 KRAS 突变通过 MEK/ERK 通路促进 bAVM 的发展，并提供了一种新的 bAVM 临床前小鼠模型，这将有助于为 bAVM 患者开发治疗策略。ANN NEUROL 2021;89:926-941。
