Immature Acta2R179C/+ Smooth Muscle Cells Cause Moyamoya-Like Cerebrovascular Lesions in Mice Prevented by Boosting OXPHOS

Authors

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
Dianna M Milewicz

Publication Date

7-2-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-61042-3

PMID

40603847

PMCID

PMC12223207

PubMedCentral® Posted Date

7-2-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Animals, Myocytes, Smooth Muscle, Moyamoya Disease, Mice, Cell Differentiation, Actins, Mitochondria, Oxidative Phosphorylation, Male, Disease Models, Animal, Cell Movement, Niacinamide, Mice, Inbred C57BL, Female, Glycolysis, Muscle, Smooth, Vascular, Humans

Published Open-Access

yes

Recommended Citation

Kaw, Anita; Majumder, Suravi; Esparza Pinelo, Jose E; et al., "Immature Acta2R179C/+ Smooth Muscle Cells Cause Moyamoya-Like Cerebrovascular Lesions in Mice Prevented by Boosting OXPHOS" (2025). Faculty, Staff and Student Publications. 4271.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4271