{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T20:06:40Z","timestamp":1789589200224,"version":"build-2803163510"},"reference-count":68,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T00:00:00Z","timestamp":1616371200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>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. <jats:italic>KRAS<\/jats:italic> 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\u2010associated virus targeting brain endothelium (AAV\u2010BR1), the current study tested if endothelial <jats:italic>KRAS<\/jats:italic><jats:sup><jats:italic>G12V<\/jats:italic><\/jats:sup> mutation induces sporadic bAVMs in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Five\u2010week\u2010old mice were systemically injected with either AAV\u2010BR1\u2010<jats:italic>GFP<\/jats:italic> or \u2010<jats:italic>KRAS<\/jats:italic><jats:sup><jats:italic>G12V<\/jats:italic><\/jats:sup>. At 8\u2009weeks after the AAV injection, bAVM formation and characteristics were addressed by histological and molecular analyses. The effect of MEK\/ERK inhibition on <jats:italic>KRAS<\/jats:italic><jats:sup><jats:italic>G12V<\/jats:italic><\/jats:sup>\u2010induced bAVMs was determined by treatment of trametinib, a US Food and Drug Administration (FDA)\u2010approved MEK\/ERK inhibitor.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The viral\u2010mediated <jats:italic>KRAS<\/jats:italic><jats:sup><jats:italic>G12V<\/jats:italic><\/jats:sup> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our innovative approach using AAV\u2010BR1 confirms that <jats:italic>KRAS<\/jats:italic> 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\u2013941<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.26059","type":"journal-article","created":{"date-parts":[[2021,3,6]],"date-time":"2021-03-06T06:38:00Z","timestamp":1615012680000},"page":"926-941","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Selective Endothelial Hyperactivation of Oncogenic <scp>KRAS<\/scp> Induces Brain Arteriovenous Malformations in Mice"],"prefix":"10.1002","volume":"89","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4213-6681","authenticated-orcid":false,"given":"Eun S.","family":"Park","sequence":"first","affiliation":[{"name":"Vivian L. Smith Department of Neurosurgery McGovern Medical School, University of Texas Health Science Center at Houston  Houston TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sehee","family":"Kim","sequence":"additional","affiliation":[{"name":"Vivian L. 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