Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM LabEx ICST, Montpellier, France.
Aix Marseille Univ, INSERM, MMG UMR1251, 13005 Marseille, France.
J Mol Cell Cardiol. 2020 Jun;143:51-62. doi: 10.1016/j.yjmcc.2020.03.013. Epub 2020 Apr 3.
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.
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.
These data indicate that the mechanosensitive ion channel piezo1 is required for outflow tract and aortic valve development.
在胚胎发生过程中，循环血流的开始会产生各种血液动力学力，这些力反过来会引起心血管发育和功能的变化。一段时间以来，人们已经知道，这些力可以被尚未可知的机械感觉系统检测到，而机械感觉系统反过来又会促进流出道和主动脉瓣等心脏发生事件的发展。PIEZO1 是一种存在于内皮细胞中的机械敏感离子通道，它用于检测血液动力学力，使其成为心脏发育过程中发挥作用的理想候选者。我们试图确定 PIEZO1 是否是流出道和主动脉瓣发育所必需的。
通过分析斑马鱼的心脏发育，我们确定 piezo1 在发育中的流出道中表达，用于检测血液动力学力。因此，破坏 Piezo1 信号会导致流出道和主动脉瓣发育缺陷，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，我们分析了来自患有左心室流出道梗阻（LVOTO）的患者的基因组数据，并在 3 名先证者中发现了 PIEZO1 中的潜在致病变异。随后的体外和体内试验表明，这些变体表现为显性负突变，导致正常 PIEZO1 机械感觉活性受到抑制。在斑马鱼内皮细胞中表达这些显性负 PIEZO1 变体导致主动脉瓣发育缺陷。
这些数据表明，机械敏感离子通道 piezo1 是流出道和主动脉瓣发育所必需的。
