Intimal thickening, caused by an accumulation of hyaluronan (HA) derived from migrated smooth muscle cells, has been reported to have an important role in the closure of the ductus arteriosus 8, 9. A previous study using pathological specimens demonstrated the presence of EPCs within the intima of occlusive arterial lesions in MMD 7. Recent laboratory studies suggest that endothelial progenitor cells (EPCs) may be important in the pathogenesis of MMD 6, 7. However, the exact mechanisms by which abnormalities in RNF213 lead to MMD remain unknown. Recent genome-wide and locus-specific association studies identified RNF213 as an important susceptibility gene for MMD 4, 5. Histopathological analyses of stenotic lesions from patients with MMD have shown eccentric fibrocellular thickening of the intima, irregular waving of the internal elastic lamina, and attenuation of the media 3. MMD affects both adults and children, and causes both ischemic and hemorrhagic stroke. These stenotic changes result in the formation of fine collateral vessels (‘moyamoya’ vessels) at the base of the brain. Moyamoya disease (MMD) is characterized by progressive stenotic changes in the terminal portion of the bilateral internal carotid arteries (ICA) 1, 2. Invading endothelial progenitor cells repairing endothelial injury would produce excessive hyaluronan and CS in the intima, and cause vascular stenosis. Because the peri-endothelial extracellular matrix plays an important role in protection, cell adhesion and migration, an altered peri-endothelial matrix in MMD may contribute to endothelial vulnerability to wall shear stress. A computational fluid dynamics model showed highest wall shear stress values in the terminal portion of the internal carotid artery, which is the predisposing region in MMD. Glycosaminoglycans of endothelial cells derived from MMD and control induced pluripotent stem cells demonstrated a decreased amount of CS, especially sulfated CS, in MMD. Furthermore, MMD lesions showed minimal staining for CS and hyaluronan in the endothelium, in contrast to control endothelium showing positive staining for both. Hyaluronan synthase 2 was strongly expressed in endothelial progenitor cells in the thickened intima. Immunohistochemical analysis of autopsy specimens from a patient with MMD revealed marked accumulation of hyaluronan and chondroitin sulfate (CS) in the thickened intima of occlusive lesions of MMD. Although RNF213 was identified as a susceptibility gene for MMD, the exact pathogenesis remains unknown. Moyamoya disease (MMD) is characterized by progressive bilateral stenotic changes in the terminal portion of the internal carotid arteries.

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