AIMS During embryogenesis, the onset of circulatory blood flow generates a variety of hemodynamic forces which reciprocally induce changes in cardiovascular development and performance. It has been known for some time that these forces can be detected by as yet unknown mechanosensory systems which in turn promote cardiogenic events such as outflow tract and aortic valve development. PIEZO1 is a mechanosensitive ion channel present in endothelial cells where it serves to detect hemodynamic forces making it an ideal candidate to play a role during cardiac development. We sought to determine whether PIEZO1 is required for outflow tract and aortic valve development. METHODS AND RESULTS By analysing heart development in zebrafish we have determined that piezo1 is expressed in the developing outflow tract where it serves to detect hemodynamic forces. Consequently, disrupting Piezo1 signalling leads to defective outflow tract and aortic valve development and indicates this gene may be involved in the etiology of congenital heart diseases. Based on these findings, we analysed genomic data generated from patients who suffer from left ventricular outflow tract obstructions (LVOTO) and identified 3 probands who each harboured potentially pathogenic variants in PIEZO1. Subsequent in vitro and in vivo assays indicates that these variants behave as dominant negatives leading to an inhibition of normal PIEZO1 mechanosensory activity. Expressing these dominant negative PIEZO1 variants in zebrafish endothelium leads to defective aortic valve development. CONCLUSION These data indicate that the mechanosensitive ion channel piezo1 is required for outflow tract and aortic valve development.

中文翻译：

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Piezo1是流出道和主动脉瓣发育所必需的。

目的在胚胎发生过程中，循环血流的产生会产生多种血流动力学力，从而相互促进心血管发育和性能的改变。一段时间以来，人们已经知道，这些力可以通过尚不为人知的机械感测系统检测到，而机械感测系统又会促进心源性事件，例如流出道和主动脉瓣的发展。PIEZO1是存在于内皮细胞中的机械敏感离子通道，可用于检测血液动力，使其成为在心脏发育过程中发挥作用的理想候选者。我们试图确定PIEZO1是否需要用于流出道和主动脉瓣的发展。方法和结果通过分析斑马鱼的心脏发育，我们确定了piezo1在发育中的流出道中表达，可用于检测血液动力。因此，破坏Piezo1信号传导导致有缺陷的流出道和主动脉瓣发育，并表明该基因可能与先天性心脏病的病因有关。基于这些发现，我们分析了患有左心室流出道梗阻（LVOTO）的患者产生的基因组数据，并确定了3个先证者，每个人在PIEZO1中都具有潜在的致病性变异。随后的体外和体内试验表明，这些变异体表现为显性负性，导致正常的PIEZO1机械感官活性受到抑制。在斑马鱼的内皮中表达这些显性负PIEZO1变异会导致有缺陷的主动脉瓣发育。结论这些数据表明机械敏感离子通道压电1是流出道和主动脉瓣发育所必需的。破坏Piezo1信号传导会导致流出道和主动脉瓣膜发育不良，并表明该基因可能与先天性心脏病的病因有关。基于这些发现，我们分析了患有左心室流出道梗阻（LVOTO）的患者产生的基因组数据，并鉴定了3个先证者，每个先证者在PIEZO1中都具有潜在的致病性变异。随后的体外和体内试验表明，这些变异体表现为显性负性，导致正常的PIEZO1机械感官活性受到抑制。在斑马鱼的内皮中表达这些显性负PIEZO1变异会导致有缺陷的主动脉瓣发育。结论这些数据表明机械敏感离子通道压电1是流出道和主动脉瓣发育所必需的。破坏Piezo1信号传导会导致流出道和主动脉瓣膜发育不良，并表明该基因可能与先天性心脏病的病因有关。基于这些发现，我们分析了患有左心室流出道梗阻（LVOTO）的患者产生的基因组数据，并鉴定了3个先证者，每个先证者在PIEZO1中都具有潜在的致病性变异。随后的体外和体内试验表明，这些变异体表现为显性负性，导致抑制正常的PIEZO1机械感官活性。在斑马鱼的内皮中表达这些显性负PIEZO1变异会导致有缺陷的主动脉瓣发育。结论这些数据表明机械敏感离子通道压电1是流出道和主动脉瓣发育所必需的。