JAG1-NOTCH4 mechanosensing drives atherosclerosis.
JAG1-NOTCH4 mechanosensing drives atherosclerosis.
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JAG1-NOTCH4机械感应驱动动脉粥样硬化。
DOI：
10.1126/sciadv.abo7958
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发表时间：
2022-09-02
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
作者：
内皮细胞（EC）对血流紊乱的感知通过不明确的机制触发动脉粥样硬化，这是一种导致心脏病发作和中风的动脉疾病。Notch通路在血管生长和体内平衡中起着核心作用，但其在感测扰动流中的潜在作用先前尚未研究。在这里，我们显示使用猪和小鼠动脉和培养的人冠状动脉EC，干扰流激活JAG 1-NOTCH 4信号通路。光片成像显示动脉粥样硬化斑块的EC中Jag 1和NOTCH 4富集，EC特异性Jag 1基因缺失（Jag 1 ECKO）表明Jag 1促进动脉粥样硬化在血流紊乱部位。从机制上讲，Jag 1 ECKO小鼠的单细胞RNA测序表明，Jag 1抑制了增殖和迁移的EC亚群。我们的结论是，JAG 1-NOTCH 4感应干扰流增强动脉粥样硬化的易感性，通过调节EC的异质性，这一途径的治疗靶向可能治疗动脉粥样硬化。复杂的血流通过激活抑制动脉修复的机械敏感性通路而促进心血管疾病。
Endothelial cell (EC) sensing of disturbed blood flow triggers atherosclerosis, a disease of arteries that causes heart attack and stroke, through poorly defined mechanisms. The Notch pathway plays a central role in blood vessel growth and homeostasis, but its potential role in sensing of disturbed flow has not been previously studied. Here, we show using porcine and murine arteries and cultured human coronary artery EC that disturbed flow activates the JAG1-NOTCH4 signaling pathway. Light-sheet imaging revealed enrichment of JAG1 and NOTCH4 in EC of atherosclerotic plaques, and EC-specific genetic deletion of Jag1 (Jag1ECKO) demonstrated that Jag1 promotes atherosclerosis at sites of disturbed flow. Mechanistically, single-cell RNA sequencing in Jag1ECKO mice demonstrated that Jag1 suppresses subsets of ECs that proliferate and migrate. We conclude that JAG1-NOTCH4 sensing of disturbed flow enhances atherosclerosis susceptibility by regulating EC heterogeneity and that therapeutic targeting of this pathway may treat atherosclerosis. Complex blood flow promotes cardiovascular disease by activating a mechanosensitive pathway that suppresses arterial repair.
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