Extracellular Vesicle miR-558 Regulates Endothelial Function Through HMGB2 in Adult Moyamoya Disease

Moyamoya disease (MMD) is a progressive cerebrovascular disorder characterized by intracranial arterial stenosis and abnormal collateral vessel formation. The molecular mechanisms by which extracellular vesicle (EV)-derived microRNAs contribute to endothelial dysfunction remain poorly understood. We investigated whether circulating extracellular vesicle-derived microRNAs (EV-miRNAs) contribute to endothelial dysfunction and serve as functional mediators of MMD pathogenesis. Plasma EV-miRNA profiles were compared among patients with MMD, intracranial atherosclerosis (ICAS), and healthy controls, and differentially expressed EV-miRNAs were validated in an independent cohort. Functional studies were performed in human umbilical vein endothelial cells and patient-derived induced pluripotent stem cell-derived endothelial cells. Three EV-miRNAs were significantly upregulated in MMD, among which miR-558 showed the strongest diagnostic performance. miR-558 overexpression impaired endothelial tube formation and proliferation, whereas its inhibition enhanced angiogenic activity. Mechanistically, HMGB2 was identified as a direct target of miR-558, and miR-558 overexpression reduced HMGB2 protein expression. Patient-derived endothelial cells recapitulated increased miR-558 expression, reduced HMGB2 levels, and impaired angiogenic capacity. These findings identify circulating EV-miR-558 a potential biomarker and show that miR-558 suppresses HMGB2 and impairs endothelial angiogenesis in adult MMD, suggesting that the EV-miR-558/HMGB2 pathway represents a potential mechanism underlying endothelial dysfunction and therapeutic target for MMD.