Mutant Kras in Brain Endothelial Cells Promotes Vascular Inflammation and Impairs Vascular Integrity in Brain Arteriovenous Malformation

Authors

Jung-Eun Park
Bridger H Freeman
Hyejin Park
Sehee Kim
Adrian E Bafor
Ohnmar Myint
Song Gao
Zhen Xu
Jakob Körbelin
Jaroslaw Aronowski
Peng Roc Chen
Eunhee Kim
Eun S Park

Language

English

Publication Date

2-16-2026

Journal

Journal of Cerebral Blood Flow & Metabolism

DOI

10.1177/0271678X261421424

PMID

41696778

PMCID

PMC12913046

PubMedCentral® Posted Date

2-16-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Somatic KRAS (KRASG12V) mutation in endothelial cells (EC) induces brain arteriovenous malformation (bAVM) that could lead to vascular instability and ultimately bleeding. However, the causes of bAVM instability remain unclear. Here we demonstrate that KRASG12V expressing cultured ECs (KRAS-G12V-EC) have increased expression of pro-inflammatory mediators and reduced expression of blood-brain-barrier (BBB) junction constituents. The conditioned medium from KRAS-G12V-EC can activate BV2-microglia (BV2-MG) and conditioned media from this primed BV2-MG can compromise the expression of EC-junction constituents when added to wild-type ECs. In an in vitro BBB model, KRAS-G12V-EC form a dysfunctional EC barrier that is further disrupted, leading to lower transendothelial electrical resistance and increased FITC-dextran leakage when blood-derived macrophages (Mφ) are included. KRAS-G12V-EC potently stimulates BV2-MG chemotaxis. In vitro BBB leakage and BV2-MG chemotaxis were inhibited by treatment with the anti-inflammatory drug minocycline in the KRAS-G12V-EC. In our bAVM mouse model that uses AAV-BR1-KRASG12V injection to produce EC expression of KRASG12V in the brain, minocycline injection reduced production of inflammatory cytokines by bAVM nidus, reduced leakage of BSA-647, and restored VE-cadherin expression on malformed vessels. Our findings suggest that KRAS-G12V-EC can activate local MG/Mφ that causes vascular inflammation and instability of malformed vessels in bAVM.

Keywords

Brain arteriovenous malformation, KRAS mutation, endothelial cells, microglia, macrophages

Published Open-Access

yes

Recommended Citation

Park, Jung-Eun; Freeman, Bridger H; Park, Hyejin; et al., "Mutant Kras in Brain Endothelial Cells Promotes Vascular Inflammation and Impairs Vascular Integrity in Brain Arteriovenous Malformation" (2026). Faculty, Staff and Student Publications. 5989.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5989