Coronary arterial development is regulated by a Dll4-Jag1-EphrinB2 signaling cascade

Abstract

Coronaries are essential for myocardial growth and heart function. Notch is crucial for mouse embryonic angiogenesis, but its role in coronary development remains uncertain. We show Jag1, Dll4 and activated Notch1 receptor expression in sinus venosus (SV) endocardium. Endocardial Jag1 removal blocks SV capillary sprouting, while Dll4 inactivation stimulates excessive capillary growth, suggesting that ligand antagonism regulates coronary primary plexus formation. Later endothelial ligand removal, or forced expression of Dll4 or the glycosyltransferase Mfng, blocks coronary plexus remodeling, arterial differentiation, and perivascular cell maturation. Endocardial deletion of Efnb2 phenocopies the coronary arterial defects of Notch mutants. Angiogenic rescue experiments in ventricular explants, or in primary human endothelial cells, indicate that EphrinB2 is a critical effector of antagonistic Dll4 and Jag1 functions in arterial morphogenesis. Thus, coronary arterial precursors are specified in the SV prior to primary coronary plexus formation and subsequent arterial differentiation depends on a Dll4-Jag1-EphrinB2 signaling cascade.

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Sequencing data have been deposited in GEO under accession codes GSE110614

The following data sets were generated

Article and author information

Author details

  1. Stanislao Igor Travisano

    Intercellular Signalling in Cardiovascular Development and Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  2. Vera Lucia Oliveira

    Intercellular Signalling in Cardiovascular Development and Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  3. Belén Prados

    Intercellular Signalling in Cardiovascular Development and Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  4. Joaquim Grego-Bessa

    Intercellular Signalling in Cardiovascular Development and Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0938-2346
  5. Rebeca Piñeiro-Sabarís

    Intercellular Signalling in Cardiovascular Development and Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  6. Vanesa Bou

    Intercellular Signalling in Cardiovascular Development and Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  7. Manuel J Gómez

    Bioinformatics, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  8. Fátima Sánchez-Cabo

    Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  9. Donal MacGrogan

    Intercellular Signalling in Cardiovascular Development and Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
    For correspondence
    dmacgrogan@cnic.es
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2808-8422
  10. José Luis De La Pompa Mínguez

    Intercellular Signalling in Cardiovascular Development and Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
    For correspondence
    jlpompa@cnic.es
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6761-7265

Funding

Spanish Ministry of Science, Innovation and Universities (SAF2016-78370-R)

  • Joaquim Grego-Bessa

Ministerio de Economía y Competitividad (CB16/11/00399)

  • José Luis De La Pompa Mínguez

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal studies were approved by the CNIC Animal Experimentation Ethics Committee and by the Madrid regional government (Ref. PROEX 118/15). All animal procedures conformed to EU Directive 2010/63EU and Recommendation 2007/526/EC regarding the protection of animals used for experimental and other scientific purposes, enforced in Spanish law under Real Decreto 1201/2005.

Reviewing Editor

  1. Bin Zhou, Chinese Academy of Sciences, China

Publication history

  1. Received: July 5, 2019
  2. Accepted: December 1, 2019
  3. Accepted Manuscript published: December 2, 2019 (version 1)
  4. Accepted Manuscript updated: December 3, 2019 (version 2)
  5. Accepted Manuscript updated: December 4, 2019 (version 3)
  6. Version of Record published: December 17, 2019 (version 4)

Copyright

© 2019, Travisano et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Stanislao Igor Travisano
  2. Vera Lucia Oliveira
  3. Belén Prados
  4. Joaquim Grego-Bessa
  5. Rebeca Piñeiro-Sabarís
  6. Vanesa Bou
  7. Manuel J Gómez
  8. Fátima Sánchez-Cabo
  9. Donal MacGrogan
  10. José Luis De La Pompa Mínguez
(2019)
Coronary arterial development is regulated by a Dll4-Jag1-EphrinB2 signaling cascade
eLife 8:e49977.
https://doi.org/10.7554/eLife.49977

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