Augmenting Mitochondrial Respiration in Immature Smooth Muscle Cells with an ACTA2 Pathogenic Variant Mitigates Moyamoya-like Cerebrovascular Disease

Abstract ACTA2 pathogenic variants altering arginine 179 cause childhood-onset strokes due to moyamoya disease (MMD)-like occlusion of the distal internal carotid arteries. A smooth muscle cell (SMC)-specific knock-in mouse model ( Acta2 SMC-R179C/+ ) inserted the mutation into 67% of aortic SMCs, whereas explanted SMCs were uniformly heterozygous. Acta2 R179C/+ SMCs fail to fully differentiate and maintain stem cell-like features, including high glycolytic flux, and increasing oxidative respiration (OXPHOS) with nicotinamide riboside (NR) drives the mutant SMCs to differentiate and decreases migration. Acta2 SMC-R179C/+ mice have intraluminal MMD-like occlusive lesions and strokes after carotid artery injury, whereas the similarly treated WT mice have no strokes and patent lumens. Treatment with NR prior to the carotid artery injury attenuates the strokes, MMD-like lumen occlusions, and aberrant vascular remodeling in the Acta2 SMC-R179C/+ mice. These data highlight the role of immature SMCs in MMD-associated occlusive disease and demonstrate that altering SMC metabolism to drive quiescence of Acta2 R179C/+ SMCs attenuates strokes and aberrant vascular remodeling in the Acta2 SMC-R179C/+ mice.