Related Experiment Video
Updated: Sep 17, 2025
A Model for Encephalomyosynangiosis Treatment after Middle Cerebral Artery Occlusion-Induced Stroke in Mice
Published on: June 22, 2022
Immature Acta2R179C/+ smooth muscle cells cause moyamoya-like cerebrovascular lesions in mice prevented by boosting
Anita Kaw1,2, Suravi Majumder1, Jose E Esparza Pinelo1
1Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Abstract:
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 Acta2R179C/+ 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 Acta2R179C/+ SMCs. Carotid artery injury of Acta2SMC-R179C/+ 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 Acta2SMC-R179C/+ mice. These data show that driving differentiation and quiescence of Acta2R179C/+ SMCs by altering cellular metabolism attenuates MMD-like disease in the Acta2SMC-R179C/+ mice, highlighting a role of immature and highly migratory SMCs in the pathogenesis of MMD.
Insights
ACTA2 gene variants cause moyamoya disease (MMD) by affecting smooth muscle cells (SMCs). Nicotinamide riboside (NR) promotes SMC differentiation, preventing MMD-like strokes in mice.
Area of Science:
- Vascular Biology
- Metabolic Regulation
- Genetics of Stroke
Background:
- ACTA2 pathogenic variants, specifically at arginine 179, are linked to childhood-onset moyamoya disease (MMD)-like strokes.
- The underlying mechanisms of MMD pathogenesis and effective preventive treatments remain largely unknown.
Purpose of the Study:
- To investigate the cellular and molecular mechanisms by which ACTA2 variants lead to MMD.
- To explore the therapeutic potential of modulating cellular metabolism in MMD.
Main Methods:
- Studied Acta2 R179C/+ smooth muscle cells (SMCs) to assess differentiation, migration, and metabolic profiles.
- Utilized a mouse model of MMD induced by carotid artery injury.
- Administered nicotinamide riboside (NR) to evaluate its effects on SMCs and MMD phenotypes in vivo.
Main Results:
- Acta2 R179C/+ SMCs exhibited impaired differentiation, increased migration, and heightened glycolytic flux.
- NR treatment promoted SMC differentiation, reduced migration, and attenuated MMD-like occlusive lesions, neurological symptoms, and neuron loss in Acta2 R179C/+ mice.
- Acta2 R179C/+ mice subjected to carotid artery injury showed premature death and MMD-like pathology, which was prevented by NR.
Conclusions:
- Immature, highly migratory SMCs driven by ACTA2 variants play a critical role in MMD pathogenesis.
- Altering cellular metabolism to promote SMC differentiation and quiescence is a promising therapeutic strategy for MMD.
