Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, United Kingdom.
Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, Leuven, Belgium.
Elife. 2020 Jun 2;9:e50684. doi: 10.7554/eLife.50684.
Mechanical force is a determinant of Notch signalling but the mechanism of force detection and its coupling to Notch are unclear. We propose a role for Piezo1 channels, which are mechanically-activated non-selective cation channels. In cultured microvascular endothelial cells, Piezo1 channel activation by either shear stress or a chemical agonist Yoda1 activated a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), a Ca-regulated transmembrane sheddase that mediates S2 Notch1 cleavage. Consistent with this observation, we found Piezo1-dependent increase in the abundance of Notch1 intracellular domain (NICD) that depended on ADAM10 and the downstream S3 cleavage enzyme, γ-secretase. Conditional endothelial-specific disruption of Piezo1 in adult mice suppressed the expression of multiple Notch1 target genes in hepatic vasculature, suggesting constitutive functional importance in vivo. The data suggest that Piezo1 is a mechanism conferring force sensitivity on ADAM10 and Notch1 with downstream consequences for sustained activation of Notch1 target genes and potentially other processes.
机械力是 Notch 信号的决定因素，但力的检测机制及其与 Notch 的偶联尚不清楚。我们提出 Piezo1 通道在其中起作用，Piezo1 通道是机械激活的非选择性阳离子通道。在培养的微血管内皮细胞中，由切应力或化学激动剂 Yoda1 激活 Piezo1 通道可激活含金属蛋白酶结构域的解整合素蛋白 10（ADAM10），ADAM10 是一种 Ca 调节的跨膜脱落酶，介导 S2 Notch1 切割。与这一观察结果一致，我们发现 Piezo1 依赖性增加 Notch1 细胞内结构域（NICD）的丰度，这依赖于 ADAM10 和下游 S3 切割酶 γ-分泌酶。成年小鼠内皮细胞特异性条件性敲除 Piezo1 可抑制肝血管中多个 Notch1 靶基因的表达，表明其在体内具有持续的功能重要性。这些数据表明，Piezo1 是一种赋予 ADAM10 和 Notch1 力敏感性的机制，其下游后果是 Notch1 靶基因的持续激活，以及潜在的其他过程。
