Study on Abnormal Angiogenesis in Moyamoya Disease via Mitochondrial D‐Loop Methylation

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Abstract
Background: Mitochondrial D‐loop methylation leads to abnormal cerebral angiogenesis. This study examines its role in vascular phenotypes of moyamoya disease (MMD). Method: Blood samples from 96 intracranial artery stenosis/occlusion (ICASO) patients (35 MMD, 61 non‐MMD) and healthy controls underwent methylation analysis. D‐loop methylation levels were analyzed using chi‐square, T ‐test, and Wilcoxon tests. Propensity score matching (PSM) adjusted for age and gender disparities. Combine clinical information with methylation data to build a diagnostic model. Further studies included the methylation levels in MMD patients carrying the RNF213 p.R4810K mutation and the methylation levels and possible mechanisms of human brain microvascular endothelial cells (hCMEC/D3) with RNF213 knockdown. Results: Healthy controls showed higher D‐loop methylation than MMD ( p < 0.05). Post‐PSM, non‐MMD ICASO patients showed higher D‐loop methylation than MMD ( p < 0.05). The AUC of the prediction model was 0.891 (95% CI, 0.821–0.961) after combining clinical information with methylation data. MMD patients with the RNF213 mutation exhibited reduced methylation at most sites, though not statistically significant ( p > 0.05). RNF213 knockout in hCMEC/D3 enhanced proliferation, migration, and tube formation, while reducing apoptosis and DNMT1 expression, leading to decreased D‐loop methylation and ROS level, increased ATP production and mitochondrial membrane potential. Conclusion: There are differences in the methylation levels in the mitochondrial D‐loop region between MMD and non‐MMD ICASO. The methylation–metabolism–angiogenesis axis may represent a promising research direction for elucidating MMD pathogenesis.

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