Circulating extracellular vesicle-derived miR-558 is upregulated in adult Moyamoya disease, suppresses HMGB2 expression, and impairs endothelial angiogenesis, identifying the EV-miR-558/HMGB2 pathway as a potential mechanism underlying endothelial dysfunction and therapeutic target for MMD.
Key Findings
Results
Three EV-miRNAs were significantly upregulated in Moyamoya disease compared to intracranial atherosclerosis and healthy controls, with miR-558 showing the strongest diagnostic performance.
Plasma EV-miRNA profiles were compared among patients with MMD, intracranial atherosclerosis (ICAS), and healthy controls.
Differentially expressed EV-miRNAs were validated in an independent cohort.
miR-558 demonstrated the strongest diagnostic performance among the three upregulated miRNAs.
The study design included both a discovery cohort and an independent validation cohort.
Results
miR-558 overexpression impaired endothelial tube formation and proliferation in human umbilical vein endothelial cells.
Functional studies were performed in human umbilical vein endothelial cells (HUVECs).
miR-558 overexpression led to impaired endothelial tube formation.
miR-558 overexpression also reduced endothelial cell proliferation.
Conversely, inhibition of miR-558 enhanced angiogenic activity, suggesting a direct regulatory role.
Results
HMGB2 was identified as a direct target of miR-558, and miR-558 overexpression reduced HMGB2 protein expression.
Mechanistic studies identified HMGB2 (High Mobility Group Box 2) as a direct target of miR-558.
Overexpression of miR-558 resulted in reduced HMGB2 protein levels.
This finding links the miR-558/HMGB2 axis to downstream impairment of endothelial angiogenesis.
The relationship was characterized as a direct targeting relationship, consistent with miRNA-mediated post-transcriptional suppression.
Functional studies were extended to patient-derived induced pluripotent stem cell-derived endothelial cells (iPSC-ECs).
These cells showed increased miR-558 expression consistent with plasma EV findings.
Reduced HMGB2 protein levels were observed in patient-derived endothelial cells.
Impaired angiogenic capacity was also recapitulated in the iPSC-EC model, supporting disease relevance of the findings.
Results
Inhibition of miR-558 enhanced angiogenic activity, suggesting the EV-miR-558/HMGB2 pathway as a potential therapeutic target in MMD.
miR-558 inhibition in endothelial cells led to enhanced angiogenic activity.
This bidirectional effect (overexpression impairing, inhibition enhancing angiogenesis) supports functional specificity of miR-558.
The authors propose the EV-miR-558/HMGB2 pathway as a potential mechanism underlying endothelial dysfunction in adult MMD.
The pathway is described as a 'potential therapeutic target for MMD.'
Results
Circulating EV-miR-558 was identified as a potential biomarker for adult Moyamoya disease.
miR-558 showed the strongest diagnostic performance among the three significantly upregulated EV-miRNAs.
The biomarker was derived from circulating plasma extracellular vesicles, suggesting non-invasive detection potential.
Validation was performed in an independent cohort, supporting the robustness of the biomarker finding.
The comparison group included ICAS patients, suggesting specificity for MMD over another cerebrovascular condition.
What This Means
Moyamoya disease (MMD) is a rare but serious brain condition where major arteries in the brain progressively narrow, cutting off blood flow and prompting the growth of fragile, abnormal blood vessels to compensate. Despite being well-described clinically, the molecular mechanisms driving this disease—particularly how the cells lining blood vessels (endothelial cells) malfunction—are not well understood. This research suggests that tiny particles called extracellular vesicles (EVs), which circulate in the blood and carry molecular messages between cells, play a role in MMD by delivering a small RNA molecule called miR-558 that disrupts normal blood vessel function.
The researchers found that miR-558 levels were significantly elevated in EVs circulating in the blood of MMD patients compared to both healthy individuals and patients with another type of blood vessel disease (intracranial atherosclerosis). In laboratory experiments using both standard endothelial cells and cells derived from MMD patients' own stem cells, increasing miR-558 levels impaired the ability of blood vessel cells to form new vessels and proliferate—processes critical for maintaining healthy vasculature. The researchers traced this effect to a protein called HMGB2, which miR-558 directly suppresses; when miR-558 is high, HMGB2 drops, and blood vessel function suffers. Importantly, blocking miR-558 reversed these effects and improved angiogenic activity, pointing toward a possible therapeutic strategy.
This research suggests that circulating EV-miR-558 could serve as a blood-based biomarker to help identify or monitor Moyamoya disease, and that the miR-558/HMGB2 pathway represents a molecular target that might be manipulated to restore normal blood vessel function. Because patient-derived stem cell models reproduced the same molecular abnormalities seen in patient blood samples, the findings have direct disease relevance. Further research will be needed to determine whether targeting this pathway is safe and effective in living organisms before clinical applications could be considered.
Kim E, Bang O, Oh G, Oh M, Lee W, Sung J, et al.. (2026). Extracellular Vesicle miR-558 Regulates Endothelial Function Through HMGB2 in Adult Moyamoya Disease.. Cells. https://doi.org/10.3390/cells15161456