Zebrafish have a remarkable ability to regenerate injured hearts. Altered hemodynamic forces after larval ventricle ablation activate the endocardial Klf2a-Notch signaling cascade to direct zebrafish cardiac regeneration. However, how the heart perceives blood flow changes and initiates signaling pathways promoting regeneration is not fully understood. The present study demonstrated that the mechanosensitive channel Trpv4 sensed the altered hemodynamic forces in injured hearts and its expression was regulated by blood flow. In addition to mediating the endocardial Klf2a-Notch signal cascade around the atrioventricular canal (AVC), we discovered that Trpv4 regulated nitric oxide (NO) signaling in the bulbus arteriosus (BA). Further experiments indicated that Notch signaling primarily acted at the early stage of regeneration, and the major role of NO signaling was at the late stage and through TGF-β pathway. Overall, our findings revealed that mechanosensitive channels perceived the changes in hemodynamics after ventricle injury, and provide novel insights into the temporal and spatial coordination of multiple signaling pathways regulating heart regeneration.

斑马鱼具有非凡的再生受损心脏的能力。幼虫心室消融后血流动力学的改变激活心内膜 Klf2a - Notch 信号级联以指导斑马鱼心脏再生。然而，心脏如何感知血流变化并启动促进再生的信号通路尚不完全清楚。本研究表明，机械敏感通道 Trpv4 能够感知受伤心脏中血流动力学的变化，并且其表达受到血流的调节。除了介导房室管 (AVC) 周围的心内膜 Klf2a-Notch 信号级联之外，我们发现 Trpv4 还调节动脉球 (BA) 中的一氧化氮 (NO) 信号传导。进一步的实验表明Notch信号主要作用于再生早期，NO信号主要在再生后期通过TGF-β途径发挥作用。总的来说，我们的研究结果表明，机械敏感通道感知心室损伤后血流动力学的变化，并为调节心脏再生的多个信号通路的时间和空间协调提供了新的见解。