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ResearchIn-Press PreviewNeuroscienceVascular biology Open Access | 10.1172/jci.insight.195638

Endothelial oncogenic KRAS mutation drives the dynamics of microglia and macrophages in brain arteriovenous malformation

Hyejin Park,1 Jung-Eun Park,1 Bridger H. Freeman,1 Bosco Seong Kyu Yang,1 Shun-Ming Ting,2 Alexander K. Suh,1 Jude P.J. Savarraj,1 Shuning Huang,3 Jakob Körbelin,4 Huimahn Alex Choi,1 Sean P. Marrelli,2 Jaroslaw Aronowski,2 Peng Roc Chen,1 Eunhee Kim,1 and Eun S. Park1

1Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

2Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

3Department of Diagnostic and Interventional Imaging, McGovern Medical Schoo, The University of Texas Health Science Center at Houston, Houston, United States of America

4Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

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1Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

2Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

3Department of Diagnostic and Interventional Imaging, McGovern Medical Schoo, The University of Texas Health Science Center at Houston, Houston, United States of America

4Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

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1Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

2Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

3Department of Diagnostic and Interventional Imaging, McGovern Medical Schoo, The University of Texas Health Science Center at Houston, Houston, United States of America

4Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

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1Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

2Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

3Department of Diagnostic and Interventional Imaging, McGovern Medical Schoo, The University of Texas Health Science Center at Houston, Houston, United States of America

4Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Yang, B. in: PubMed | Google Scholar

1Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

2Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

3Department of Diagnostic and Interventional Imaging, McGovern Medical Schoo, The University of Texas Health Science Center at Houston, Houston, United States of America

4Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Ting, S. in: PubMed | Google Scholar

1Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

2Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

3Department of Diagnostic and Interventional Imaging, McGovern Medical Schoo, The University of Texas Health Science Center at Houston, Houston, United States of America

4Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

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1Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

2Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

3Department of Diagnostic and Interventional Imaging, McGovern Medical Schoo, The University of Texas Health Science Center at Houston, Houston, United States of America

4Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Savarraj, J. in: PubMed | Google Scholar

1Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

2Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

3Department of Diagnostic and Interventional Imaging, McGovern Medical Schoo, The University of Texas Health Science Center at Houston, Houston, United States of America

4Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Huang, S. in: PubMed | Google Scholar

1Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

2Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

3Department of Diagnostic and Interventional Imaging, McGovern Medical Schoo, The University of Texas Health Science Center at Houston, Houston, United States of America

4Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Körbelin, J. in: PubMed | Google Scholar |

1Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

2Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

3Department of Diagnostic and Interventional Imaging, McGovern Medical Schoo, The University of Texas Health Science Center at Houston, Houston, United States of America

4Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Choi, H. in: PubMed | Google Scholar

1Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

2Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

3Department of Diagnostic and Interventional Imaging, McGovern Medical Schoo, The University of Texas Health Science Center at Houston, Houston, United States of America

4Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Marrelli, S. in: PubMed | Google Scholar |

1Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

2Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

3Department of Diagnostic and Interventional Imaging, McGovern Medical Schoo, The University of Texas Health Science Center at Houston, Houston, United States of America

4Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Aronowski, J. in: PubMed | Google Scholar

1Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

2Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

3Department of Diagnostic and Interventional Imaging, McGovern Medical Schoo, The University of Texas Health Science Center at Houston, Houston, United States of America

4Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Chen, P. in: PubMed | Google Scholar

1Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

2Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

3Department of Diagnostic and Interventional Imaging, McGovern Medical Schoo, The University of Texas Health Science Center at Houston, Houston, United States of America

4Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Kim, E. in: PubMed | Google Scholar

1Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

2Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States of America

3Department of Diagnostic and Interventional Imaging, McGovern Medical Schoo, The University of Texas Health Science Center at Houston, Houston, United States of America

4Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Park, E. in: PubMed | Google Scholar

Published February 5, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.195638.
Copyright © 2026, Park et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 5, 2026 - Version history
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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.

Graphical Abstract
graphical abstract
Supplemental material

View Supplemental Table 1. Human bAVM tissues and controls were used for Figure 2.

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View Supplemental Table 2. Re-analyzed immune cell proportion (Winkler et al.,)

View Supplemental Table 3. Re-analyzed exp. stats_Microglia_AIF1 (Winkler et al.,)

View Supplemental Table 4. Re-analyzed exp. stats_Microglia_CD68 (Winkler et al.,)

View Supplemental Table 5. Re-analyzed exp. stats_Macrophages_AIF1 (Winkler et al.,)

View Supplemental Table 6. Re-analyzed exp. stats_Macrophages_CD68 (Winkler et al.,)

View Supplemental Table 7. Systolic blood pressure during treatment periods.

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Version history
  • Version 1 (February 5, 2026): In-Press Preview
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