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Coronary arteries form by developmental reprogramming of venous cells

Nature volume 464, pages 549–553 (2010)Cite this article

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Abstract

Coronary artery disease is the leading cause of death worldwide. Determining the coronary artery developmental program could aid understanding of the disease and lead to new treatments, but many aspects of the process, including their developmental origin, remain obscure. Here we show, using histological and clonal analysis in mice and cardiac organ culture, that coronary vessels arise from angiogenic sprouts of the sinus venosus—the vein that returns blood to the embryonic heart. Sprouting venous endothelial cells dedifferentiate as they migrate over and invade the myocardium. Invading cells differentiate into arteries and capillaries; cells on the surface redifferentiate into veins. These results show that some differentiated venous cells retain developmental plasticity, and indicate that position-specific cardiac signals trigger their dedifferentiation and conversion into coronary arteries, capillaries and veins. Understanding this new reprogramming process and identifying the endogenous signals should suggest more natural ways of engineering coronary bypass grafts and revascularizing the heart.

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Figure 1: Coronary vessels sprout from the sinus venosus.
Figure 2: Analysis of coronary vessel sprouting in vitro.
Figure 3: Clonal analysis of coronary artery development.
Figure 4: Downregulation of venous markers and induction of arterial markers during coronary artery development.

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Acknowledgements

We thank T. Quertermous, L. Iruela-Arispe and S. M. Evans for mouse strains, Krasnow laboratory members for input and comments, especially M. Kumar for guidance on clonal analysis, and C. Breitweiser and M. Petersen for help preparing figures. K.R.-H. was supported by the National Institutes of Health under Ruth L. Kirschstein National Research Service Award (2T32HD007249). M.A.K. is an investigator of the Howard Hughes Medical Institute.

Author Contributions K.R.-H. designed and performed all experiments. K.R.-H. and M.A.K. analysed the experiments and wrote the manuscript. H.U. and I.L.W. provided the multicolour reporter mice and advised on its use.

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Authors and Affiliations

  1. Department of Biochemistry and Howard Hughes Medical Institute,,

    Kristy Red-Horse & Mark A. Krasnow

  2. Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305-5307, USA ,

    Hiroo Ueno & Irving L. Weissman

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  1. Kristy Red-Horse
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Correspondence to Mark A. Krasnow.

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Supplementary information

Supplementary Information

This file contains Supplementary Figures S1-10 with legends and Supplementary Table S1. (PDF 25390 kb)

Supplementary Movie 1

This file contains a timelapse video (10 frames/sec) of intact heart cultured for 72 hours. (MOV 2994 kb)

Supplementary Movie 2

This file contains a timelapse video (10 frames/sec) of dissected ventricle cultured for 72 hours. (MOV 550 kb)

Supplementary Movie 3

This file contains a timelapse video (10 frames/sec) of dissected atria cultured for 72 hours. (MOV 248 kb)

Supplementary Movie 4

This file contains a timelapse video (10 frames/sec) of recombined heart cultured for 72 hours. (MOV 2145 kb)

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Red-Horse, K., Ueno, H., Weissman, I. et al. Coronary arteries form by developmental reprogramming of venous cells. Nature 464, 549–553 (2010). https://doi.org/10.1038/nature08873

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