CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common form of genetic stroke and vascular dementia syndrome resulting from mutations in NOTCH3. To elucidate molecular mechanisms of the condition and identify drug targets, we established a patient-specific induced pluripotent stem cell (iPSC) model and demonstrated for the first time a failure of the patient iPSC-derived vascular mural cells (iPSC-MCs) in engaging and stabilizing endothelial capillary structures. The patient iPSC-MCs had reduced platelet-derived growth factor receptor β, decreased secretion of the angiogenic factor vascular endothelial growth factor (VEGF), were highly susceptible to apoptotic insults, and could induce apoptosis of adjacent endothelial cells. Supplementation of VEGF significantly rescued the capillary destabilization. Small interfering RNA knockdown of NOTCH3 in iPSC-MCs revealed a gain-of-function mechanism for the mutant NOTCH3. These disease mechanisms likely delay brain repair after stroke in CADASIL, contributing to the brain hypoperfusion and dementia in this condition, and will help to identify potential drug targets.

CADASIL（伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病）是最常见的由NOTCH3 基因突变引起的遗传性中风和血管性痴呆综合征. 为了阐明该病症的分子机制并确定药物靶点，我们建立了患者特异性诱导多能干细胞 (iPSC) 模型，并首次证明患者 iPSC 衍生的血管壁细胞 (iPSC-MC) 无法参与并稳定内皮毛细血管结构。患者 iPSC-MC 的血小板衍生生长因子受体 β 减少，血管生成因子血管内皮生长因子 (VEGF) 的分泌减少，对凋亡损伤高度敏感，并可诱导邻近内皮细胞凋亡。VEGF 的补充显着挽救了毛细血管不稳定。iPSC-MC 中NOTCH3的小干扰 RNA 敲低揭示了突变体NOTCH3的功能获得机制. 这些疾病机制可能会延迟 CADASIL 中风后的大脑修复，导致这种情况下的大脑灌注不足和痴呆，并将有助于确定潜在的药物靶点。