RNF213 loss-of-function promotes pathological angiogenesis in moyamoya disease via the Hippo pathway

Area of Science:

• Cerebrovascular biology
• Genetics of rare diseases
• Endothelial cell function

Background:

• Moyamoya disease is a rare cerebrovascular disorder with unknown pathogenesis.
• Ring finger protein 213 (RNF213) is a key susceptibility gene, particularly in Asian populations.
• The precise role of RNF213 mutations in moyamoya disease development requires further elucidation.

Purpose of the Study:

• To investigate the functional impact of RNF213 mutations on moyamoya disease pathogenesis.
• To explore the molecular mechanisms by which RNF213 loss-of-function affects vascular development.
• To identify potential therapeutic targets by analyzing RNF213's role in endothelial cell signaling.

Main Methods:

• Whole-genome sequencing of patient samples and RNF213 mutation analysis.
• In vivo studies using RNF213-deficient mouse and zebrafish models.
• In vitro experiments involving RNF213 knockdown in human brain microvascular endothelial cells.
• Bioinformatics analysis of RNA-seq data and validation of signaling pathways.

Main Results:

• Pathogenic RNF213 mutations correlate with moyamoya disease histopathology.
• RNF213 deficiency exacerbates pathological angiogenesis in both animal models and cell cultures.
• Reduced RNF213 expression enhances endothelial cell proliferation, migration, and tube formation.
• RNF213 knockdown activates the Hippo pathway (YAP/TAZ) and upregulates VEGFR2, promoting angiogenesis.

Conclusions:

• Loss-of-function mutations in RNF213 are implicated in moyamoya disease pathogenesis.
• The Hippo pathway and VEGFR2 signaling are critical mediators of RNF213's role in angiogenesis.
• RNF213's regulation of endothelial cell behavior via the Hippo pathway presents a potential therapeutic avenue for moyamoya disease.