Vulnerability to shear stress caused by altered peri-endothelial matrix is a key feature of Moyamoya disease

Area of Science:

• Vascular Biology
• Biochemistry
• Genetics

Background:

• Moyamoya disease (MMD) is a progressive cerebrovascular disorder characterized by stenosis in the terminal internal carotid arteries.
• The exact pathogenesis of MMD remains unclear, despite the identification of RNF213 as a susceptibility gene.

Purpose of the Study:

• To investigate the role of glycosaminoglycans (GAGs), specifically hyaluronan and chondroitin sulfate (CS), in the pathogenesis of Moyamoya disease.
• To explore the relationship between endothelial progenitor cells, extracellular matrix composition, and vascular stenosis in MMD.

Main Methods:

• Immunohistochemical analysis of autopsy specimens from an MMD patient and controls.
• Analysis of glycosaminoglycans in endothelial cells derived from MMD and control induced pluripotent stem cells.
• Computational fluid dynamics modeling to assess wall shear stress in the internal carotid artery.

Main Results:

• MMD lesions showed marked accumulation of hyaluronan and CS in the thickened intima, with high hyaluronan synthase 2 expression in endothelial progenitor cells.
• MMD endothelium exhibited minimal staining for CS and hyaluronan compared to controls.
• Endothelial cells from MMD patients had reduced amounts of CS, especially sulfated CS.
• Computational fluid dynamics identified high wall shear stress in the predisposing arterial region for MMD.

Conclusions:

• Altered peri-endothelial extracellular matrix composition, including excessive hyaluronan and CS production by invading endothelial progenitor cells, may contribute to endothelial vulnerability and vascular stenosis in Moyamoya disease.
• These findings suggest a novel mechanism involving GAG dysregulation in MMD pathogenesis.