Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease with unknown etiology. Recent genome-wide and locus-specific association studies identified RNF213 as an important MMD susceptibility gene. However, the exact mechanism by which an abnormality in RNF213 leads to MMD is unknown. To evaluate the role of RNF213 in the etiology of MMD, we generated RNF213-deficient mice (RNF213-/-) by deleting exon 32 of RNF213 by the Cre-lox system, and investigated whether they developed MMD. The temporal profile of cervical/intracranial arteries was evaluated by 9.4-T magnetic resonance angiography (MRA). The anatomy of the circle of Willis was analyzed by a trans-cardiac injection of carbon black dye. The common carotid arteries (CCA) were sectioned and the arterial wall thickness/thinness was evaluated by Elastica-Masson staining before and after CCA ligation, which selectively induced vascular hyperplasia. As a result, RNF213-/- grew normally, and no significant difference was observed in MRA findings, the anatomy of the circle of Willis, or vascular wall thickness/thinness between RNF-/- and wild-type littermates (Wt.) under normal conditions until 64 weeks of age. However, Elastica-Masson staining demonstrated that both the intima and medial layer were significantly thinner after CCA ligation in RNF213-/- than in Wt. after 14 days (P<0.01). In conclusion, mice lacking the RNF213 gene did not spontaneously develop MMD, indicating that a functional loss of RNF213 did not sufficiently induce MMD. Suppression of vascular remodeling in RNF213-/- requires further examination to clarify the role of RNF213.
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