School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
School of Biomedical Sciences, University of Leeds, Leeds, LS2 9JT, UK.
Commun Biol. 2023 Apr 1;6(1):358. doi: 10.1038/s42003-023-04706-4.
Two prominent concepts for the sensing of shear stress by endothelium are the PIEZO1 channel as a mediator of mechanically activated calcium ion entry and the PECAM1 cell adhesion molecule as the apex of a triad with CDH5 and VGFR2. Here, we investigated if there is a relationship. By inserting a non-disruptive tag in native PIEZO1 of mice, we reveal in situ overlap of PIEZO1 with PECAM1. Through reconstitution and high resolution microscopy studies we show that PECAM1 interacts with PIEZO1 and directs it to cell-cell junctions. PECAM1 extracellular N-terminus is critical in this, but a C-terminal intracellular domain linked to shear stress also contributes. CDH5 similarly drives PIEZO1 to junctions but unlike PECAM1 its interaction with PIEZO1 is dynamic, increasing with shear stress. PIEZO1 does not interact with VGFR2. PIEZO1 is required in Ca-dependent formation of adherens junctions and associated cytoskeleton, consistent with it conferring force-dependent Ca entry for junctional remodelling. The data suggest a pool of PIEZO1 at cell junctions, the coming together of PIEZO1 and PECAM1 mechanisms and intimate cooperation of PIEZO1 and adhesion molecules in tailoring junctional structure to mechanical requirement.
两种突出的内皮细胞感知切应力的概念是作为机械激活钙离子内流介质的 PIEZO1 通道和作为与 CDH5 和 VGFR2 三聚体顶点的 PECAM1 细胞黏附分子。在这里，我们研究了它们之间是否存在关系。通过在小鼠天然 PIEZO1 中插入非破坏标记，我们揭示了 PIEZO1 与 PECAM1 的原位重叠。通过重组和高分辨率显微镜研究，我们表明 PECAM1 与 PIEZO1 相互作用，并将其引导至细胞-细胞连接处。PECAM1 的细胞外 N 端在此过程中至关重要，但与切应力相关的细胞内 C 端结构域也有贡献。CDH5 也同样将 PIEZO1 驱动至连接处，但与 PECAM1 不同，它与 PIEZO1 的相互作用是动态的，随着切应力的增加而增加。PIEZO1 与 VGFR2 不相互作用。PIEZO1 是 Ca 依赖性黏附连接形成和相关细胞骨架所必需的，这与它赋予连接重塑的力依赖性 Ca 内流一致。这些数据表明，在细胞连接处存在 PIEZO1 池，PIEZO1 和 PECAM1 机制的汇聚以及 PIEZO1 和黏附分子在调整连接结构以适应机械需求方面的密切合作。
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