Driessen R C H, Stassen O M J A, Sjöqvist M, Suarez Rodriguez F, Grolleman J, Bouten C V C, Sahlgren C M
Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
Integr Biol (Camb). 2018 Nov 12;10(11):719-726. doi: 10.1039/c8ib00036k.
Notch signaling and blood flow regulate vascular formation and maturation, but how shear stress affects the different components of the Notch pathway in endothelial cells is poorly understood. We show that laminar shear stress results in a ligand specific gene expression profile in endothelial cells (HUVEC). JAG1 expression increases while DLL4 expression decreases. Jagged1 shows a unique response by clustering intracellularly six to nine hours after the onset of flow. The formation of the Jagged1 clusters requires protein production, ER export and endocytosis. Clustering is associated with reduced membrane levels but is not affected by Notch signaling activity. Jagged1 relocalization is reversible, the clusters disappear and membrane levels increase upon removal of shear stress. We further demonstrate that the signaling potential of endothelial cells is enhanced after exposure to shear stress. Together we demonstrate a Jagged1 specific shear stress response for Notch signaling in endothelial cells.
Notch信号通路和血流调节血管的形成与成熟，但剪切应力如何影响内皮细胞中Notch信号通路的不同组分却鲜为人知。我们发现层流剪切应力在内皮细胞（人脐静脉内皮细胞）中导致了一种配体特异性的基因表达谱。JAG1表达增加而DLL4表达降低。在血流开始后六至九小时，Jagged1在内细胞内聚集，表现出独特的反应。Jagged1聚集体的形成需要蛋白质合成、内质网输出和内吞作用。聚集与膜水平降低相关，但不受Notch信号活性的影响。Jagged1的重新定位是可逆的，去除剪切应力后聚集体消失且膜水平增加。我们进一步证明，暴露于剪切应力后内皮细胞的信号传导潜能增强。我们共同证明了内皮细胞中Notch信号存在一种Jagged1特异性的剪切应力反应。
