Spatial and temporal variations in hemodynamic forces initiate cardiac trabeculation

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Biophysics

Background:

• Hemodynamic forces, specifically wall shear stress (WSS), are known to influence cellular processes.
• Notch signaling plays a critical role in cardiac development, including trabeculation.
• The precise coordination of WSS and Notch signaling in cardiac trabeculation remains unclear.

Purpose of the Study:

• To investigate how spatiotemporal variations in WSS regulate Notch signaling during cardiac trabeculation.
• To determine the impact of WSS-mediated trabeculation on ventricular contractile function.

Main Methods:

• Utilized light-sheet fluorescent microscopy for 4D reconstruction of the developing zebrafish heart.
• Applied computational fluid dynamics to quantify 4D WSS patterns.
• Employed genetic manipulations to alter WSS and Notch signaling (e.g., γ-Secretase inhibitor).

Main Results:

• Identified distinct WSS patterns (pulsatile vs. oscillatory) in trabecular ridges and grooves.
• Correlated specific WSS patterns with endocardial and epicardial Notch activity at different developmental stages (3-4 dpf).
• Demonstrated that modulating WSS affects Notch activity and cardiomyocyte proliferation, and that Notch inhibition/rescue impacts trabeculation.

Conclusions:

• Spatiotemporal variations in WSS are crucial for coordinating cardiac trabeculation.
• WSS-mediated Notch signaling regulates cardiomyocyte proliferation and trabecular organization.
• Trabeculation, influenced by WSS, is essential for preserving ventricular structure and contractile function.