School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria, Australia.
Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
J Cell Physiol. 2021 Apr;236(4):2976-2987. doi: 10.1002/jcp.30056. Epub 2020 Sep 22.
Mechanosensitive ion channels mediate endothelial responses to blood flow and orchestrate their physiological function in response to hemodynamic forces. In this study, we utilized microfluidic technologies to study the shear-induced sensitization of endothelial Piezo-1 to its selective agonist, Yoda-1. We demonstrated that shear stress-induced sensitization is brief and can be impaired when exposing aortic endothelial cells to low and proatherogenic levels of shear stress. Our results suggest that shear stress-induced sensitization of Piezo-1 to Yoda-1 is independent of cell-cell adhesion and is mediated by the PI3K-AKT signaling pathway. We also found that shear stress increases the membrane density of Piezo-1 channels in endothelial cells. To further confirm our findings, we performed experiments using a carotid artery ligation mouse model and demonstrated that transient changes in blood-flow pattern, resulting from a high-degree ligation of the mouse carotid artery alters the distribution of Piezo-1 channels across the endothelial layer. These results suggest that shear stress influences the function of Piezo-1 channels via changes in membrane density, providing a new model of shear-stress sensitivity for Piezo-1 ion channel.
机械敏感离子通道介导内皮细胞对血流的反应，并协调其生理功能以响应血流动力。在这项研究中，我们利用微流控技术研究了剪切诱导内皮细胞 Piezo-1 对其选择性激动剂 Yoda-1 的敏感性。我们证明，剪切应力诱导的敏感性是短暂的，并且当将主动脉内皮细胞暴露于低和致动脉粥样硬化水平的剪切应力下时，这种敏感性会受损。我们的结果表明，Piezo-1 对 Yoda-1 的剪切应力诱导敏感性独立于细胞-细胞黏附，并由 PI3K-AKT 信号通路介导。我们还发现，剪切应力增加了内皮细胞中 Piezo-1 通道的膜密度。为了进一步证实我们的发现，我们使用颈动脉结扎小鼠模型进行了实验，并证明由于小鼠颈动脉高度结扎导致的血流模式的短暂变化改变了 Piezo-1 通道在内皮层中的分布。这些结果表明，剪切应力通过改变膜密度来影响 Piezo-1 通道的功能，为 Piezo-1 离子通道提供了一种新的剪切应力敏感性模型。
