Immature Acta2(R179C/+) smooth muscle cells cause moyamoya-like cerebrovascular lesions in mice prevented by boosting OXPHOS.

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