An Rnf213-deficient hypoperfusion model reveals Moyamoya-relevant neurovascular remodeling

Moyamoya disease (MMD) is a chronic cerebrovascular disorder characterized by progressive stenosis of the terminal portions of the bilateral internal carotid arteries and their major branches, accompanied by the development of an abnormal vascular network at the base of the brain. Although RNF213 is the major susceptibility gene, its relatively low penetrance in MMD suggests that genetic predisposition requires synergistic interaction with environmental stressors to induce the characteristic pathological vascular remodeling. Studies have demonstrated that patients with MMD exhibit mild stenosis of the common carotid artery (CCA) diameter. Furthermore, a reduction in CCA diameter is associated with an increase in cerebral blood volume and a prolongation of mean transit time. Based on this novel clinical finding, we established a mouse model combining Rnf213 knockout with bilateral common carotid artery stenosis. These mice exhibited hypoperfusion-induced neurovascular remodeling with moyamoya-relevant features, including cerebral hemorrhage, infarction, and extensive proliferation of fragile microvessels. Mechanistically, RNF213 knockdown sensitizes cerebral vessels to hypoperfusion stress and promotes the proliferation and migration of brain microvascular endothelial cells in the absence of shear stress. In conclusion, these results link Rnf213 deficiency with mild CCA stenosis under hypoperfusion stress, providing additional insights into the complex systemic manifestations of MMD pathogenesis.