Intracardiac flow dynamics regulate atrioventricular valve morphogenesis
Intracardiac flow dynamics regulate atrioventricular valve morphogenesis
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DOI：
10.1093/cvr/cvu186
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发表时间：
2014-10-01
影响因子：
10.8
通讯作者：
Beis, Dimitris
中科院分区：
文献类型：
--
作者：
Kalogirou, Stamatia;Malissovas, Nikos;Beis, Dimitris
目的瓣膜性心脏病的发病率和死亡率相当高。心脏瓣膜随着心脏收缩而发育，它们在生物体的整个生命周期中发挥作用，以防止逆行血流。它们精确的形态发生对心脏功能至关重要。斑马鱼是研究心脏瓣膜发育的理想模型，因为它允许通过非侵入性成像在体内进行这些研究。越来越多的证据表明，心脏瓣膜发育中收缩力和心内血流动力学的作用。然而，这两个因素已被证明很难脱钩，特别是因为改变心肌功能影响心内的流动patterns.Methods和结果在这里，我们描述了新的斑马鱼模型的发展瓣膜缺陷。我们发现了两个肌球蛋白重链6的突变等位基因，尽管只有一个功能室-心室，但它们可以被抚养到成年。成年突变心室经历重塑，房室（AV）瓣膜未能形成四个尖瓣。与此同时，我们的特点是一种新的突变等位基因的左撇子，一个与左，右不对称，表现出随机的心脏和内胚层定位的建立相关的基因。我们首先观察到，在左撇子突变体中，两个心腔的相对位置被改变，影响心脏的几何形状，而心肌功能似乎不受影响。突变的心脏，环正确或表现出原位逆发展正常，而中线，unlooped心脏表现出缺陷，在他们的跨瓣流动模式在AV瓣膜的发展，以及在valve morphogenesis.Conclusion缺陷我们的数据表明，心内血流动力学调节瓣膜形态独立的心肌收缩力。
Aims Valvular heart disease is responsible for considerable morbidity and mortality. Cardiac valves develop as the heart contracts, and they function throughout the lifetime of the organism to prevent retrograde blood flow. Their precise morphogenesis is crucial for cardiac function. Zebrafish is an ideal model to investigate cardiac valve development as it allows these studies to be carried out in vivo through non-invasive imaging. Accumulating evidence suggests a role for contractility and intracardiac flow dynamics in cardiac valve development. However, these two factors have proved difficult to uncouple, especially since altering myocardial function affects the intracardiac flow pattern.Methods and results Here, we describe novel zebrafish models of developmental valve defects. We identified two mutant alleles of myosin heavy chain 6 that can be raised to adulthood despite having only one functional chamber-the ventricle. The adult mutant ventricle undergoes remodelling, and the atrioventricular (AV) valves fail to form four cuspids. In parallel, we characterized a novel mutant allele of southpaw, a nodal-related gene involved in the establishment of left-right asymmetry, which exhibits randomized heart and endoderm positioning. We first observed that in southpaw mutants the relative position of the two cardiac chambers is altered, affecting the geometry of the heart, while myocardial function appears unaffected. Mutant hearts that loop properly or exhibit situs inversus develop normally, whereas midline, unlooped hearts exhibit defects in their transvalvular flow pattern during AV valve development as well as defects in valve morphogenesis.Conclusion Our data indicate that intracardiac flow dynamics regulate valve morphogenesis independently of myocardial contractility.