Spatiotemporal modulation of nitric oxide and Notch signaling by hemodynamic-responsive Trpv4 is essential for ventricle regeneration

Abstract

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.

A novel gene-trap line reveals the dynamic patterns and essential roles of cysteine and glycine-rich protein 3 in zebrafish heart development and regeneration

“…Previous studies demonstrated that Csrp3 played an essential role in the CM stretch sensor machinery [ 2 ], and was required for mechanical stability in skeletal muscles [ 27 ]. We recently showed mechanotransduction is critical for zebrafish heart regeneration [ 28 ]. Thus, we also assessed the expression of several genes involved in mechanotransduction process in ablated 218A larval hearts.…”