{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T03:57:38Z","timestamp":1779249458280,"version":"3.51.4"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Brain arteriovenous malformations (bAVMs) are a major risk factor for intracerebral hemorrhages in young patients. Recent clinical studies have reported that the majority of human bAVMs harbor somatic KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations. In our previous study, we confirmed the causal role of endothelial KRAS\n                      <jats:sup>G12V<\/jats:sup>\n                      mutation in bAVM development in mice through hyperactivation of the MEK\/ERK (mitogen-activated protein kinase kinase\/extracellular signal\u2013regulated kinase) pathway. However, the treatment efficacy of targeting MEK\/ERK signaling in bAVMs, regarding clinical and biological outcomes, remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      In this study, we used the US Food and Drug Administration\u2013approved MEK inhibitor, trametinib, to treat mice with bAVMs induced by brain endothelial cell (EC)\u2013specific KRAS\n                      <jats:sup>G12V<\/jats:sup>\n                      overexpression (KRAS\n                      <jats:sup>G12V\/bEC<\/jats:sup>\n                      mice). We treated KRAS\n                      <jats:sup>G12V\/bEC<\/jats:sup>\n                      mice with either vehicle or trametinib and evaluated outcomes on mortality and the alteration of bAVMs, and the hemorrhages. We also determined the effect of trametinib on the endothelial-to-mesenchymal transition, which has recently been explored in human bAVMs and implicated in bAVM pathology, in bAVMs of KRAS\n                      <jats:sup>G12V\/bEC<\/jats:sup>\n                      mice and cultured mouse ECs transfected with KRAS\n                      <jats:sup>G12V<\/jats:sup>\n                      (EC\n                      <jats:sup>G12V<\/jats:sup>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We observed that trametinib significantly improved survivability, potentially through improved vessel integrity and reduction in the severity of bAVM ruptures. Our longitudinal observation of mice bAVMs using noninvasive magnetic resonance imaging revealed that trametinib decreased the total hemorrhagic volume at 8 weeks of treatment when administered at 1 mg\/kg compared with the vehicle group, which was confirmed by histological analyses. In addition, trametinib altered endothelial-to-mesenchymal transition by reducing the expression levels of mesenchymal markers (N-Cad [N-cadherin], Slug, CD44 [cluster of differentiation 44]) and increasing an EC marker (VE-Cad [vascular endothelial cadherin]) in bAVMs of KRAS\n                      <jats:sup>G12V\/bEC<\/jats:sup>\n                      mice. Trametinib also decreased proliferation (Ki-67) and angiogenic (CD34 and pVEGFR2 [phosphor-vascular endothelial growth factor receptor 2]) markers in KRAS\n                      <jats:sup>G12V\/bEC<\/jats:sup>\n                      mice\u2019s bAVMs. We also confirmed that trametinib normalized the endothelial-to-mesenchymal transition-associated marker expression and functions in EC\n                      <jats:sup>G12V<\/jats:sup>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our data demonstrate that trametinib improves bAVM pathology by reducing hemorrhagic risk and normalizing endothelial-to-mesenchymal transition. These findings suggest that trametinib is a promising agent to treat patients with bAVM.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.125.052418","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T10:00:15Z","timestamp":1766052015000},"page":"779-793","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Trametinib Decreased Intracerebral Hemorrhages and Endothelial-to-Mesenchymal Transition in KRAS\n                    <sup>G12V<\/sup>\n                    -Induced Brain Arteriovenous Malformations in Mice"],"prefix":"10.1161","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9004-4282","authenticated-orcid":true,"given":"Ohnmar","family":"Myint","sequence":"first","affiliation":[{"name":"Vivian L. Smith Department of Neurosurgery, McGovern Medical School (O.M., B.H.F., J.J., H.P., S.M.W., J.E.P., E.S.P., P.R.C., E.K.), The University of Texas Health Science Center at Houston."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bridger H.","family":"Freeman","sequence":"additional","affiliation":[{"name":"Vivian L. Smith Department of Neurosurgery, McGovern Medical School (O.M., B.H.F., J.J., H.P., S.M.W., J.E.P., E.S.P., P.R.C., E.K.), The University of Texas Health Science Center at Houston."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5163-0004","authenticated-orcid":true,"given":"Jaeyeong","family":"Jeong","sequence":"additional","affiliation":[{"name":"Vivian L. Smith Department of Neurosurgery, McGovern Medical School (O.M., B.H.F., J.J., H.P., S.M.W., J.E.P., E.S.P., P.R.C., E.K.), The University of Texas Health Science Center at Houston."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5326-9711","authenticated-orcid":true,"given":"Hyejin","family":"Park","sequence":"additional","affiliation":[{"name":"Vivian L. Smith Department of Neurosurgery, McGovern Medical School (O.M., B.H.F., J.J., H.P., S.M.W., J.E.P., E.S.P., P.R.C., E.K.), The University of Texas Health Science Center at Houston."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha M.","family":"Wilfur","sequence":"additional","affiliation":[{"name":"Vivian L. Smith Department of Neurosurgery, McGovern Medical School (O.M., B.H.F., J.J., H.P., S.M.W., J.E.P., E.S.P., P.R.C., E.K.), The University of Texas Health Science Center at Houston."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuning","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Imaging, McGovern Medical School (S.H.), The University of Texas Health Science Center at Houston."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9216-3719","authenticated-orcid":true,"given":"Jung-Eun","family":"Park","sequence":"additional","affiliation":[{"name":"Vivian L. Smith Department of Neurosurgery, McGovern Medical School (O.M., B.H.F., J.J., H.P., S.M.W., J.E.P., E.S.P., P.R.C., E.K.), The University of Texas Health Science Center at Houston."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5435-7182","authenticated-orcid":true,"given":"Jakob","family":"K\u00f6rbelin","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Germany (J.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9256-7973","authenticated-orcid":true,"given":"Jaroslaw","family":"Aronowski","sequence":"additional","affiliation":[{"name":"Department of Neurology, McGovern Medical School (J.A.), The University of Texas Health Science Center at Houston."},{"name":"Center for Neuroimmunology and Glial Biology, The Brown Foundation Institute of Molecular Medicine (J.A., E.S.P.), The University of Texas Health Science Center at Houston."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4213-6681","authenticated-orcid":true,"given":"Eun S.","family":"Park","sequence":"additional","affiliation":[{"name":"Vivian L. Smith Department of Neurosurgery, McGovern Medical School (O.M., B.H.F., J.J., H.P., S.M.W., J.E.P., E.S.P., P.R.C., E.K.), The University of Texas Health Science Center at Houston."},{"name":"Center for Neuroimmunology and Glial Biology, The Brown Foundation Institute of Molecular Medicine (J.A., E.S.P.), The University of Texas Health Science Center at Houston."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8438-132X","authenticated-orcid":true,"given":"Peng Roc","family":"Chen","sequence":"additional","affiliation":[{"name":"Vivian L. Smith Department of Neurosurgery, McGovern Medical School (O.M., B.H.F., J.J., H.P., S.M.W., J.E.P., E.S.P., P.R.C., E.K.), The University of Texas Health Science Center at Houston."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7755-7291","authenticated-orcid":true,"given":"Eunhee","family":"Kim","sequence":"additional","affiliation":[{"name":"Vivian L. Smith Department of Neurosurgery, McGovern Medical School (O.M., B.H.F., J.J., H.P., S.M.W., J.E.P., E.S.P., P.R.C., E.K.), The University of Texas Health Science Center at Houston."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/124.10.1900"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000069012.23858.69"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.3171\/jns.1990.73.3.0387"},{"key":"e_1_3_3_5_2","first-page":"171","volume-title":"Handbook of Clinical Neurology","author":"Rutledge C","year":"2021","unstructured":"Rutledge C, Cooke DL, Hetts SW, Abla AA. Chapter 10\u2014brain arteriovenous malformations. In: Hetts SW, Cooke DL, eds. Handbook of Clinical Neurology. 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