Augmenting Mitochondrial Respiration in Immature Smooth Muscle Cells with an <i>ACTA2</i> 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

SUBMITTER: Kaw A 

PROVIDER: S-EPMC10602100 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature