Selective Endothelial Hyperactivation of Oncogenic KRAS Induces Brain Arteriovenous Malformations in Mice

摘要: Objective Brain arteriovenous malformations (bAVMs) are a leading cause of hemorrhagic stroke and neurological deficits in children young adults, however, no pharmacological intervention is available to treat these patients. Although more than 95% bAVMs sporadic without family history, the pathogenesis largely unknown, which may account for lack therapeutic options. KRAS mutations frequently observed cancer, recent unprecedented finding human offers new direction bAVM research. Using novel adeno-associated virus targeting brain endothelium (AAV-BR1), current study tested if endothelial KRASG12V mutation induces mice. Methods Five-week-old mice were systemically injected with either AAV-BR1-GFP or -KRASG12V . At 8 weeks after AAV injection, formation characteristics addressed by histological molecular analyses. The effect MEK/ERK inhibition on -induced was determined treatment trametinib, US Food Drug Administration (FDA)-approved inhibitor. Results viral-mediated overexpression induced bAVMs, composed tangled nidus mirroring distinctive morphology bAVMs. accompanied focal angiogenesis, intracerebral hemorrhages, altered vascular constituents, neuroinflammation, impaired sensory/cognitive/motor functions. Finally, we confirmed that growth inhibited trametinib treatment. Interpretation Our innovative approach using AAV-BR1 confirms promote development via pathway, provides preclinical mouse model will be useful develop strategy patients bAVM. ANN NEUROL 2021;89:926-941.