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