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 profiles1,2. 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.
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Acknowledgements
We thank S. Lin for the stable transgenic gata1::GFP zebrafish strain, E. Walsh, E. Ober, B. Jungblut and D.Y.R. Stainier for the transgenic tie2::GFP strain and comments on the manuscript and M. Bak and Y. Gong for discussions. This work was supported by the American Heart Association (J.R.H.) and the Human Frontier Science Program (R.W.K.), the NIH (S.E.F.), the Beckman Institute at Caltech and the Powell Foundation. J.R.H. worked on flow pattern analysis and calculations. R.W.K. worked on imaging and embryonic manipulation.
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Supplementary information
41586_2003_BFnature01282_MOESM2_ESM.mov
Supplementary Movie 2: Dynamics of heart valves in 4.5dpf old homozygous tie2::GFP transgenic zebrafish embryos. (MOV 746 kb)
41586_2003_BFnature01282_MOESM9_ESM.mov
Supplementary Movie 9: Cardiac dynamics in homozygous tie2::GFP transgenic zebrafish embryos at 4.5dpf after continuously blocking blood influx into the heart. (MOV 724 kb)
41586_2003_BFnature01282_MOESM10_ESM.mov
Supplementary Movie 10: Cardiac dynamics in homozygous tie2::GFP transgenic zebrafish embryos at 4.5dpf after continuously blocking blood efflux out of the heart. (MOV 643 kb)
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Hove, J., Köster, R., Forouhar, A. et al. Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis. Nature 421, 172–177 (2003). https://doi.org/10.1038/nature01282
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DOI: https://doi.org/10.1038/nature01282
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