Background: Moyamoya disease (MMD) is a unique cerebrovascular occlusive disease of unknown etiology. Ring finger protein 213 (RNF213) was identified as a susceptibility gene for MMD in East Asian. However, the pathogenesis of MMD is still unclear.
Methods: We prospectively analyzed clinical data for 139 patients with MMD (108 definite MMD, 31 probable MMD) and 61 patients with intracranial atherosclerotic stroke (ICAS), and 68 healthy subjects. We compared the genetic (RNF213 variant) and protein biomarkers for caveolae (caveolin-1), angiogenesis (vascular endothelial growth factor [VEGF] and receptor [VEGFR2], and antagonizing cytokine [endostatin]) and endothelial dysfunction (asymmetric dimethylarginine [ADMA], nitric oxide and its metabolites [nitrite and nitrate]), between patients with MMD and ICAS. We then performed the path analysis to evaluate whether a certain protein biomarker mediates the association the genetic and MMD.
Results: Caveolin-1 level was decreased in patients with MMD and this level was markedly decreased in RNF213 variant carriers. Circulating factor such as VEGF and receptor were not different among the groups. Markers for endothelial dysfunction were significantly higher in patients with ICAS, but normal in MMD. The path analysis showed that the presence of the RNF213 variant was associated with caveolin-1 level that led to MMD. The level of combined marker of MMD (caveolin-1) and ICAS (ADMA, marker for endothelial dysfunction) predicted MMD with a good sensitivity and specificity.
Conclusions: Our results indicate that MMD is primarily caveolae disorder, dysregulation of endothelial vesicular trafficking and signal transduction, but not related to endothelial dysfunction or dysregulation of circulating cytokines.