PDF(Pubmed)
Abstract：
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.
摘要：
内皮细胞（EC）对血流紊乱的感知会引发动脉粥样硬化，一种引起心脏病和中风的动脉疾病，通过定义不清的机制。Notch通路在血管生长和体内平衡中起着核心作用，但其在扰动流感知中的潜在作用尚未得到研究。这里,我们显示使用猪和鼠动脉和培养的人冠状动脉EC，干扰血流激活JAG1-NOTCH4信号通路。光片成像显示JAG1和NOTCH4在动脉粥样硬化斑块的EC中富集，和Jag1的EC特异性遗传缺失（Jag1ECKO）表明Jag1促进了血流紊乱部位的动脉粥样硬化。机械上,Jag1ECKO小鼠中的单细胞RNA测序表明Jag1抑制增殖和迁移的ECs亚群。我们得出的结论是，JAG1-NOTCH4对血流紊乱的感知通过调节EC异质性来增强动脉粥样硬化的易感性，并且该途径的治疗靶向可以治疗动脉粥样硬化。
