Abstract 12624: Smooth Muscle Cell Alpha-Actin Pathogenic Variant That Predisposes to Moyamoya-Like Cerebrovascular Disease Alters Smooth Muscle Cell Phenotype and Metabolism

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Pathogenic variants in ACTA2 , which encodes smooth muscle α-actin ( α-SMA ), predispose to thoracic aortic disease. ACTA2 variants disrupting arginine 179 ( R179 ) also predispose to moyamoya-like ( MMD ) cerebrovascular disease, characterized by occlusion of the distal internal carotid arteries by neointimal cells that stain positive for smooth muscle cell ( SMC ) markers. Mice with conditional knockin of the Acta2 R179C mutation specifically in SMCs were generated ( Acta2 SMC-R179C/+ ). RNA sequencing and 2D gel electrophoresis confirmed presence of the mutation. Acta2 SMC-R179C/+ SMCs are not fully differentiated, maintain stem cell marker expression, and proliferate and migrate faster than wildtype ( WT ) SMCs. Seahorse analyses show increased glycolysis and decreased oxidative respiration ( OXPHOS ) in Acta2 SMC-R179C/+ SMCs, which have reduced mitochondrial mass and complex I activity, suggestive of deficient electron transport chain activity. Nicotinamide riboside ( NR ) augments complex I activity to boost OXPHOS without altering mitochondrial mass in Acta2 SMC-R179C/+ SMCs. NR also increases differentiation and reduces migration in Acta2 SMC-R179C/+ SMCs. With left carotid artery ligation ( LCAL ), 33% of Acta2 SMC-R179C/+ mice die within 4 days due to strokes, and 100% of surviving Acta2 SMC-R179C/+ mice at postop day 21 have occlusive lesions in the injured artery (8% in WT mice) containing α-SMA+ cells and fibrin deposits. Acta2 SMC-R179C/+ mice also exhibit markedly increased left carotid artery diameter and increased number, diameter, and tortuosity of left-sided collateral vessels compared to WT mice at postop day 21. NR treatment reduces deaths of LCAL-injured Acta2 SMC-R179C/+ mice to 8%, completely resolves occlusive lesion formation in 50% of mutant mice, and attenuates collateral formation and remodeling. These data suggest that immature SMCs with the ACTA2 R179C variant proliferate and migrate into the neointima causing MMD-like occlusive disease. Shifting metabolism to OXPHOS with NR drives differentiation and reduces migration, which diminishes arterial lesions in Acta2 SMC-R179C/+ mice. These data support the use of NR as a therapeutic to prevent MMD-like lesions and ischemic strokes in children with ACTA2 p.R179 variants.