Faculty, Staff and Student Publications

Language

English

Publication Date

12-18-2025

Journal

Stroke

DOI

10.1161/STROKEAHA.125.052418

PMID

41410028

PMCID

PMC12768455

PubMedCentral® Posted Date

1-6-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Background: 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 mutations. In our previous study, we confirmed the causal role of endothelial KRASG12V mutation in bAVM development in mice through hyperactivation of the MEK/ERK (extracellular signal-regulated kinase) pathway. However, the treatment efficacy of targeting MEK/ERK signaling in bAVMs, regarding clinical and biological outcomes, remains unclear.

Methods: In this study, we used the Food and Drug Administration-approved MEK inhibitor, trametinib, to treat mice with bAVMs induced by brain endothelial cell (EC)-specific KRASG12V overexpression (KRASG12V/bEC [mice injected with adeno-associated viral-BR1-KRASG12V] mice). We treated KRASG12V/bEC 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 KRASG12V/bEC mice and cultured mouse ECs transfected with KRASG12V (ECG12V [EC transfected with the hKRASG12V gene]).

Results: 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) and increasing an EC marker (VE-Cad [vascular endothelial cadherin]) in bAVMs of KRASG12V/bEC mice. Trametinib also decreased proliferation (Ki-67) and angiogenic (CD34 and pVEGFR2) markers in KRASG12V/bEC mice's bAVMs. We also confirmed that trametinib normalized the endothelial-to-mesenchymal transition-associated marker expression and functions in ECG12V.

Conclusions: 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.

Keywords

brain Arteriovenous malformations (bAVMs), Trametinib, Endothelial cells (ECs), Endothelial-to-mesenchymal transition (EndMT)

Published Open-Access

yes

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