Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis

Abstract

The pattern of blood flow in the developing heart has long been proposed to play a significant role in cardiac morphogenesis. In response to flow-induced forces, cultured cardiac endothelial cells rearrange their cytoskeletal structure and change their gene expression profiles. To link such in vitro data to the intact heart, we performed quantitative in vivo analyses of intracardiac flow forces in zebrafish embryos. Using in vivo imaging, here we show the presence of high-shear, vortical flow at two key stages in the developing heart, and predict flow-induced forces much greater than might have been expected for micro-scale structures at low Reynolds numbers. To test the relevance of these shear forces in vivo, flow was occluded at either the cardiac inflow or outflow tracts, resulting in hearts with an abnormal third chamber, diminished looping and impaired valve formation. The similarity of these defects to those observed in some congenital heart diseases argues for the importance of intracardiac haemodynamics as a key epigenetic factor in embryonic cardiogenesis.

Integrated Regional Cardiac Hemodynamic Imaging and RNA Sequencing Reveal Corresponding Heterogeneity of Ventricular Wall Shear Stress and Endocardial Transcriptome

“…Flow is essential for successful heart and valve formation, in which endothelial phenotype programming plays a central role 4, 38. Flow may continue to define the EEC phenotype in the fully mature heart against a “fixed” developmental background.…”

Rapid three‐dimensional imaging and analysis of the beating embryonic heart reveals functional changes during development

“…For instance, blocking flow through the zebrafish heart leads to severe dysmorphology (Hove et al, 2003), and mutants that lack contractile function in the early heart also have defects in valve formation and show an absence of endocardial thickening at the AV boundary (Sehnert et al, 2002;Bartman et al, 2004). Presently, it is not clear whether morphology is genetically determined and blood flow adapts to this environment or if blood flow plays a role in sculpting the morphology of the heart.…”

“…In the zebrafish, cardiac progenitors from both sides of the midline fuse and give rise to a luminized heart tube; the heart begins to beat at the linear tube stage, moving blood cells through this conduit, before the emergence of clearly defined heart chambers, valves, or septae (Stainier and Fishman, 1994;Trinh and Stainier, 2004). The vertebrate heart develops in the presence of mechanical and hemodynamic stimuli; thus, the question arises whether the structure of the heart influences its function, or, conversely, whether the flows and mechanical forces in the heart influence its form (Hove et al, 2003;Bartman et al, 2004;Beis et al, 2005). Although a great number of methods have been developed to understand the genetic contributions to heart formation, methods to study epigenetic contributions have been difficult to establish, mainly because of rapid motions that are involved (typically millimeters per second for distances of a few hundred microns).…”

Probing events with single molecule sensitivity in zebrafish and Drosophila embryos by fluorescence correlation spectroscopy

“…Mechanical signals such as shear stress induced by blood flow is essential for normal development of organs involved in circulation (Hove et al, 2003;Korzh et al, 2008). Currently, several approaches have been implemented to measure flow velocities in small animal vessels, e.g.…”