Mechanically activated piezo channels modulate outflow tract valve development through the Yap1 and Klf2-Notch signaling axis.

Anne-Laure Duchemin,Julien Vermot,Hélène Vignes

doi:10.7554/elife.44706

Abstract

Mechanical forces are well known for modulating heart valve developmental programs. Yet, it is still unclear how genetic programs and mechanosensation interact during heart valve development. Here, we assessed the mechanosensitive pathways involved during zebrafish outflow tract (OFT) valve development in vivo. Our results show that the hippo effector Yap1, Klf2, and the Notch signaling pathway are all essential for OFT valve morphogenesis in response to mechanical forces, albeit active in different cell layers. Furthermore, we show that Piezo and TRP mechanosensitive channels are important factors modulating these pathways. In addition, live reporters reveal that Piezo controls Klf2 and Notch activity in the endothelium and Yap1 localization in the smooth muscle progenitors to coordinate OFT valve morphogenesis. Together, this work identifies a unique morphogenetic program during OFT valve formation and places Piezo as a central modulator of the cell response to forces in this process.

Highlights

Heart pumping and shaping take place concomitantly during embryonic development
Outflow tract valve morphogenesis is unique In order to better understand the roles played by blood flow during outflow tract (OFT) valve development, we have developed imaging techniques to capture cardiac motion and analyze blood flow in the OFT
We identify two tissue layers sensitive to mechanical forces in the OFT: (1) The endothelial cells where klf2a expression is modulated both by Piezo and transient potential channels (Trp) channels (2) The smooth muscles surrounding the endothelium, where Piezo channels regulate Yap1 localization and smooth muscle cell specific marker expression (Figure 9)

Summary

Introduction

Heart pumping and shaping take place concomitantly during embryonic development. These two processes require a tight and dynamic coordination between mechanical forces and tissue morphogenesis. Abnormalities of the arterial valve leaflets are the most-common congenital malformations, in particular bicuspid aortic valve (Hoffman and Kaplan, 2002). Aortic valves mainly derive from endocardial cushion progenitors with a potential contribution from other cellular sources (epicardial cells and neural crest) (Wu et al, 2017). Recent evidences suggest that arterial valves develop differently from atrioventricular valves by differentiating directly from progenitors in the outflow wall independently from endMT in mouse (Eley et al, 2018)

Methods

Results

Conclusion