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<p><i>ACTA2</i> 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 <i>Acta2</i><sup><i>R179C/+</i></sup> 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 <i>Acta2</i><sup><i>R179C/+</i></sup> SMCs. Carotid artery injury of <i>Acta2</i><sup><i>SMC-R179C/+</i></sup> 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 <i>Acta2</i><sup><i>SMC-R179C/+</i></sup> mice. These data show that driving differentiation and quiescence of <i>Acta2</i><sup><i>R179C/+</i></sup> SMCs by altering cellular metabolism attenuates MMD-like disease in the <i>Acta2</i><sup><i>SMC-R179C/+</i></sup> mice, highlighting a role of immature and highly migratory SMCs in the pathogenesis of MMD.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月2日

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  • 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

摘要

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.