Endothelial Oncogenic Kras Mutation Drives the Dynamics of Microglia and Macrophages in Brain Arteriovenous Malformation

Authors

Hyejin Park
Jung-Eun Park
Bridger H Freeman
Bosco Seong Kyu Yang
Shun-Ming Ting
Alexander K Suh
Jude Pj Savarraj
Shuning Huang
Jakob Körbelin
Huimahn Alex Choi
Sean P Marrelli
Jaroslaw Aronowski
Peng Roc Chen
Eunhee Kim
Eun S Park

Language

English

Publication Date

2-5-2026

Journal

JCI Insight

DOI

10.1172/jci.insight.195638

PMID

41642659

Abstract

Mutation of KRAS in endothelial cells (KRAS-EC) leads to intracerebral hemorrhage (ICH) in brain arteriovenous malformations (bAVM), resulting in severe disabilities or even death. However, it is unclear what causes this hemorrhagic conversion of bAVM. Here, using a locally established, clinically-relevant sporadic bAVM mouse model, created by overexpressing mutant KRAS (KRASG12V) in the brain EC, we demonstrate that KRAS-EC act as trigger for microglia (MG) activation and infiltration of macrophages (Mϕ). Using three-dimensional immunostaining approach with cleared human and mouse bAVM tissues, we demonstrate an abundance of MG/Mϕ around the bAVM nidus. The presence of MG/Mϕ are correlated to the blood-brain barrier leakage in bAVM area. Time-lapsed intravital imaging in Cx3cr1-gfp;Ccr2-rfp reporter mice demonstrate the dynamic activation of MG and infiltration of Mϕ toward mutant KRAS-modified dysplastic vessels. Importantly, a time course analysis showed that these activated/infiltrated MG/Mϕ are present around the bAVMs prior to hemorrhagic conversion, and controlled depletion of MG/Mϕ reduced ICH incidence in bAVM. Inhibition of MG/Mϕ with long-term minocycline treatment attenuated the incidence of ICHs around bAVMs. Our study indicates that MG/Mϕ are involved in destabilization of KRAS-induced bAVM, leading to hemorrhagic conversion/ICH. Thus, modulation of MG/Mϕ may reduce ICH risk in bAVM patients.

Keywords

Endothelial cells, Macrophages, Neuroscience, Stroke, Vascular biology

Published Open-Access

yes

Recommended Citation

Park, Hyejin; Park, Jung-Eun; Freeman, Bridger H; et al., "Endothelial Oncogenic Kras Mutation Drives the Dynamics of Microglia and Macrophages in Brain Arteriovenous Malformation" (2026). Faculty, Staff and Student Publications. 5290.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5290