Piezo1 acts upstream of TRPV4 to induce pathological changes in endothelial cells due to shear stress.
Piezo1 acts upstream of TRPV4 to induce pathological changes in endothelial cells due to shear stress.
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DOI：
10.1074/jbc.ra120.015059
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Liddle RA
中科院分区：
文献类型：
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作者：
Swain SM;Liddle RA
离子通道Piezo1和TRPV4都独立地与高静脉压和流体剪切应力诱导的内皮细胞血管通透性过高有关。然而，Piezo1和TRPV4通道执行相同功能的机制知之甚少。在这里，我们表明，Piezo1调节TRPV4通道激活内皮细胞和Piezo1介导的TRPV4通道开放是流体剪切应力的强度和持续时间的函数。我们首先证实，无论是流体剪切应力或Piezo1激动剂，Yoda1，导致细胞内钙（[Ca2+]i）的升高和应用Piezo1拮抗剂，GsMTx4，完全阻断了这种变化。我们发现，高和长时间的剪切应力引起持续的[Ca2+]i升高，通过抑制TRPV4通道开放来阻断。此外，Piezo1通过激活磷脂酶A2刺激TRPV4开放。TRPV4依赖的持续[Ca2+]i升高是流体剪切应力介导和Piezo 1介导的粘附连接破坏和肌动蛋白重塑的原因。用选择性TRPV4阻断剂HC067047阻断TRPV4通道，可防止Yoda 1或剪切应力诱导的内皮细胞完整性丧失和肌动蛋白破坏，并防止Piezo 1诱导的单核细胞粘附到内皮细胞单层。这些研究结果表明，流体剪切应力激活Piezo1启动钙信号，导致TRPV4开放，这反过来又导致持续阶段钙升高，触发内皮细胞的病理事件。因此，剪切应力的有害影响由Piezo1引发，但需要TRPV4。
The ion channels Piezo1 and TRPV4 have both, independently, been implicated in high venous pressure– and fluid shear stress–induced vascular hyperpermeability in endothelial cells. However, the mechanism by which Piezo1 and TRPV4 channels execute the same function is poorly understood. Here we demonstrate that Piezo1 regulates TRPV4 channel activation in endothelial cells and that Piezo1-mediated TRPV4 channel opening is a function of the strength and duration of fluid shear stress. We first confirmed that either fluid shear stress or the Piezo1 agonist, Yoda1, led to an elevation in intracellular calcium ([Ca2+]i) and that application of the Piezo1 antagonist, GsMTx4, completely blocked this change. We discovered that high and prolonged shear stress caused sustained [Ca2+]i elevation that was blocked by inhibition of TRPV4 channel opening. Moreover, Piezo1 stimulated TRPV4 opening through activation of phospholipase A2. TRPV4-dependent sustained [Ca2+]i elevation was responsible for fluid shear stress–mediated and Piezo1-mediated disruption of adherens junctions and actin remodeling. Blockade of TRPV4 channels with the selective TRPV4 blocker, HC067047, prevented the loss of endothelial cell integrity and actin disruption induced by Yoda1 or shear stress and prevented Piezo1-induced monocyte adhesion to endothelial cell monolayers. These findings demonstrate that Piezo1 activation by fluid shear stress initiates a calcium signal that causes TRPV4 opening, which in turn is responsible for the sustained phase calcium elevation that triggers pathological events in endothelial cells. Thus, deleterious effects of shear stress are initiated by Piezo1 but require TRPV4.