Abstract
Myocardial contractility and blood flow provide essential mechanical cues for the morphogenesis of the heart. In general, endothelial cells change their migratory behavior in response to shear stress patterns, according to flow directionality. Here, we assessed the impact of shear stress patterns and flow directionality on the behavior of endocardial cells, the specialized endothelial cells of the heart. At the early stages of zebrafish heart valve formation, we show that endocardial cells are converging to the valve-forming area and that this behavior depends upon mechanical forces. Quantitative live imaging and mathematical modeling allow us to correlate this tissue convergence with the underlying flow forces. We predict that tissue convergence is associated with the direction of the mean wall shear stress and of the gradient of harmonic phase-averaged shear stresses, which surprisingly do not match the overall direction of the flow. This contrasts with the usual role of flow directionality in vascular development and suggests that the full spatial and temporal complexity of the wall shear stress should be taken into account when studying endothelial cell responses to flow in vivo.
Highlights
After the first heartbeat, a directional blood flow is established in the embryonic cardiovascular system
To identify the morphogenetic response of endocardial cells (EdCs) to shear stress patterns in vivo, we examined the early events of the formation of the atrioventricular canal (AVC), which is the area between the forming atrium and ventricle, where the valve will develop and where strong local spatial and temporal gradients are expected
Considering that these cells will contribute to the AVC valve structure (Steed et al, 2016b; Pestel et al, 2016), these results suggest that the convergence of EdCs toward the AVC might be the first morphogenetic step of heart valve morphogenesis
Summary
After the first heartbeat, a directional blood flow is established in the embryonic cardiovascular system. The tangential force generated by fluid flow at the cell surface can be characterized in terms of shear stress (Freund et al, 2012). Oscillatory shear stress has been shown to modulate the expression of klf2a, an important flow-responsive gene for heart chamber (Dietrich et al, 2014) and valve development (Vermot et al, 2009; Heckel et al, 2015; Steed et al, 2016a). It is not clear, F.B., 0000-0002-6338-6321; E.S., 0000-0003-4742-2860; J.B.F., 0000-00027073-1365; J.V., 0000-0002-8924-732X
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