Abstract 11906: Targeting Metabolic Alterations in Smooth Muscle Cells Associated With an Acta2 Pathogenic Variant Prevents Moyamoya-Like Cerebrovascular Disease

Abstract

Listen

Translate article

Pathogenic variants disrupting arginine 179 ( R179 ) in ACTA2 (encodes smooth muscle α-actin) predispose to moyamoya ( MMD )-like cerebrovascular disease, characterized by occlusion of the distal internal carotid arteries by cells that stain positive for smooth muscle cell ( SMC ) markers. SMCs explanted from mice with a SMC-specific knock-in of the Acta2 R179C mutation ( Acta2 SMC-R179C/+ [PMID: 35878552]) fail to fully differentiate, maintain stem cell marker expression, and proliferate and migrate faster than wild-type ( WT ) SMCs. Consistent with a stem cell-like phenotype, Seahorse assays and metabolomics analyses found that Acta2 SMC-R179C/+ SMCs have increased glycolytic flux and decreased oxidative respiration ( OXPHOS ) associated with reduced mitochondrial DNA ( mtDNA ) and complex I activity when compared to WT SMCs. Exposing Acta2 SMC-R179C/+ SMCs to nicotinamide riboside ( NR ), a NAD+ analogue, decreases glycolysis and increases OXPHOS by enhancing complex I activity, and with this metabolic switch, Acta2 SMC-R179C/+ SMCs increase differentiation and decrease migration. With left carotid artery ligation ( LCAL ), 21% of Acta2 SMC-R179C/+ mice die of strokes within 5 days, and at postop day 21, 100% of the surviving Acta2 SMC-R179C/+ mice have enlarged left carotid arteries occluded with cells positive for SMC marker; compared to only 8% of the WT mice. The Acta2 SMC-R179C/+ mice 21 days post LCAL also have increased leptomeningeal collateral remodeling and Circle of Willis (CoW) narrowing and straightening based on CT imaging with liposomal-iodinated contrast agent. NR treatment reduces deaths with LCAL in the mutant mice (p=0.20), resolves intraluminal occlusive lesion formation (p<0.05), attenuates CoW narrowing and straightening (p<0.05), and prevents aberrant collateral remodeling (p<0.001). These results define the pathogenesis of MMD lesions associated with ACTA2 R179 variants: the mutation disrupts the differentiation of stem cells into SMCs, leading to increased SMC migration and proliferation and MMD-like lesions with LCAL, and identify a potential therapeutic that alters SMC metabolism to drive differentiation and decrease migration, and ultimately attenuate MMD-like cerebrovascular disease in Acta2 SMC-R179C/+ mice.