Obstructive arterial diseases, including supravalvular aortic stenosis (SVAS), atherosclerosis, and restenosis, share 2 important features: an abnormal or disrupted elastic lamellae structure and excessive smooth muscle cells (SMCs). However, the relationship between these pathological features is poorly delineated. SVAS is caused by heterozygous loss-of-function, hypomorphic, or deletion mutations in the elastin gene (ELN), and SVAS patients and elastin-mutant mice display increased arterial wall cellularity and luminal obstructions. Pharmacological treatments for SVAS are lacking, as the underlying pathobiology is inadequately defined. Herein, using human aortic vascular cells, mouse models, and aortic samples and SMCs derived from induced pluripotent stem cells of ELN-deficient patients, we demonstrated that elastin insufficiency induced epigenetic changes, upregulating the NOTCH pathway in SMCs. Specifically, reduced elastin increased levels of γ-secretase, activated NOTCH3 intracellular domain, and downstream genes. Notch3 deletion or pharmacological inhibition of γ-secretase attenuated aortic hypermuscularization and stenosis in Eln^–/– mutants. Eln^–/– mice expressed higher levels of NOTCH ligand JAGGED1 (JAG1) in aortic SMCs and endothelial cells (ECs). Finally, Jag1 deletion in SMCs, but not ECs, mitigated the hypermuscular and stenotic phenotype in the aorta of Eln^–/– mice. Our findings reveal that NOTCH3 pathway upregulation induced pathological aortic SMC accumulation during elastin insufficiency and provide potential therapeutic targets for SVAS.

中文翻译：

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JAGGED1/NOTCH3 激活促进主动脉过度肌肉化和弹性蛋白缺乏症的狭窄

阻塞性动脉疾病，包括主动脉瓣上狭窄 (SVAS)、动脉粥样硬化和再狭窄，有两个重要特征：异常或破坏的弹性片层结构和过多的平滑肌细胞 (SMC)。然而，这些病理特征之间的关系还不清楚。SVAS 是由弹性蛋白基因 ( ELN )中的杂合性功能丧失、亚形态或缺失突变引起的，SVAS 患者和弹性蛋白突变小鼠表现出动脉壁细胞结构增加和管腔阻塞。缺乏对 SVAS 的药理学治疗，因为其潜在的病理学定义不充分。在此，使用人主动脉血管细胞、小鼠模型和主动脉样本以及源自ELN的诱导多能干细胞的 SMC- 缺陷患者，我们证明弹性蛋白不足引起表观遗传变化，上调 SMC 中的 NOTCH 通路。具体而言，减少的弹性蛋白会增加 γ-分泌酶、激活的 NOTCH3 细胞内结构域和下游基因的水平。Notch3缺失或 γ-分泌酶的药理学抑制减弱了Eln ^–/–突变体中的主动脉过度肌肉化和狭窄。Eln ^–/–小鼠在主动脉平滑肌细胞和内皮细胞 (EC) 中表达更高水平的 NOTCH 配体 JAGGED1 (JAG1)。最后， SMCs 中的Jag1缺失，而不是 ECs，减轻了Eln主动脉的过度肌肉和狭窄表型^–/–老鼠。我们的研究结果表明，NOTCH3 通路上调在弹性蛋白功能不全期间诱导病理性主动脉 SMC 积聚，并为 SVAS 提供潜在的治疗靶点。