Immature Acta2R179C/+ smooth muscle cells cause moyamoya-like cerebrovascular lesions in mice prevented by boosting OXPHOS

Anita Kaw, Suravi Majumder, Jose E. Esparza Pinelo, Ting Wu, Zbigniew Starosolski, Zhen Zhou, Albert J. Pedroza, Xueyan Duan, Kaveeta Kaw, Angie D. Gonzalez, Ripon Sarkar, Michael P. Fischbein, Philip L. Lorenzi, Lin Tan, Sara A. Martinez, Iqbal Mahmud, Laxman Devkota, L. Maximilian Buja, Heinrich Taegtmeyer, Ketan B. Ghaghada, Sean P. Marrelli, Callie S. Kwartler () and Dianna M. Milewicz ()
Additional contact information
Anita Kaw: The University of Texas Health Science Center at Houston
Suravi Majumder: The University of Texas Health Science Center at Houston
Jose E. Esparza Pinelo: The University of Texas Health Science Center at Houston
Ting Wu: The University of Texas Health Science Center at Houston
Zbigniew Starosolski: Texas Children’s Hospital
Zhen Zhou: The University of Texas Health Science Center at Houston
Albert J. Pedroza: Stanford University School of Medicine
Xueyan Duan: The University of Texas Health Science Center at Houston
Kaveeta Kaw: The University of Texas Health Science Center at Houston
Angie D. Gonzalez: The University of Texas Health Science Center at Houston
Ripon Sarkar: The University of Texas Health Science Center at Houston
Michael P. Fischbein: Stanford University School of Medicine
Philip L. Lorenzi: The University of Texas MD Anderson Cancer Center
Lin Tan: The University of Texas MD Anderson Cancer Center
Sara A. Martinez: The University of Texas MD Anderson Cancer Center
Iqbal Mahmud: The University of Texas MD Anderson Cancer Center
Laxman Devkota: Texas Children’s Hospital
L. Maximilian Buja: The University of Texas Health Science Center at Houston
Heinrich Taegtmeyer: The University of Texas Health Science Center at Houston
Ketan B. Ghaghada: Texas Children’s Hospital
Sean P. Marrelli: The University of Texas Health Science Center at Houston
Callie S. Kwartler: The University of Texas Health Science Center at Houston
Dianna M. Milewicz: The University of Texas Health Science Center at Houston

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract ACTA2 pathogenic variants altering arginine 179 cause childhood-onset strokes due to moyamoya disease (MMD)-like occlusions of the distal internal carotid arteries, but the mechanisms of pathogenesis are unknown and no preventive treatments exist. Here we show that Acta2R179C/+ smooth muscle cells (SMCs) fail to fully differentiate and maintain stem cell-like features, including increased migration and glycolytic flux compared to wildtype (WT) SMCs. Increasing mitochondrial respiration with nicotinamide riboside (NR) drives differentiation and decreases migration of Acta2R179C/+ SMCs. Carotid artery injury of Acta2SMC-R179C/+ mice leads to premature death, intraluminal SMC accumulation leading to MMD-like occlusive lesions, neurologic symptoms, and neuron loss, whereas injured WT mice have none of these phenotypes, and all are prevented by NR treatment in the Acta2SMC-R179C/+ mice. These data show that driving differentiation and quiescence of Acta2R179C/+ SMCs by altering cellular metabolism attenuates MMD-like disease in the Acta2SMC-R179C/+ mice, highlighting a role of immature and highly migratory SMCs in the pathogenesis of MMD.

Date: 2025
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DOI: 10.1038/s41467-025-61042-3

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