1. Developmental Biology
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Apelin signaling drives vascular endothelial cells towards a pro-angiogenic state

  1. Christian SM Helker  Is a corresponding author
  2. Jean Eberlein
  3. Kerstin Wilhelm
  4. Toshiya Sugino
  5. Julian Malchow
  6. Annika Schuermann
  7. Stefan Baumeister
  8. Hyouk-Bum Kwon
  9. Hans-Martin Maischein
  10. Michael Potente
  11. Wiebke Herzog
  12. Didier YR Stainier  Is a corresponding author
  1. Philipps-University Marburg, Germany
  2. Max Planck Institute for Heart and Lung Research, Germany
  3. University of Muenster, Germany
Research Article
  • Cited 7
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Cite this article as: eLife 2020;9:e55589 doi: 10.7554/eLife.55589

Abstract

To form new blood vessels (angiogenesis), endothelial cells (ECs) must be activated and acquire highly migratory and proliferative phenotypes. However, the molecular mechanisms that govern these processes are incompletely understood. Here, we show that Apelin signaling functions to drive ECs into such an angiogenic state. Zebrafish lacking Apelin signaling exhibit defects in endothelial tip cell morphology and sprouting. Using transplantation experiments, we find that in mosaic vessels, wild-type ECs leave the dorsal aorta (DA) and form new vessels while neighboring ECs defective in Apelin signaling remain in the DA. Mechanistically, Apelin signaling enhances glycolytic activity in ECs at least in part by increasing levels of the growth-promoting transcription factor c-Myc. Moreover, Apelin expression is regulated by Notch signaling, and its function is required for the hypersprouting phenotype in Delta-like 4 (Dll4) knockdown embryos. These data provide new insights into fundamental principles of blood vessel formation and Apelin signaling, enabling a better understanding of vascular growth in health and disease.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Christian SM Helker

    Faculty of Biology, Philipps-University Marburg, Marburg, Germany
    For correspondence
    christian.helker@biologie.uni-marburg.de
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0427-5338
  2. Jean Eberlein

    Faculty of Biology, Philipps-University Marburg, Marburg, Germany
    Competing interests
    No competing interests declared.
  3. Kerstin Wilhelm

    Angiogenesis and Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  4. Toshiya Sugino

    Angiogenesis and Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6330-7275
  5. Julian Malchow

    Faculty of Biology, Philipps-University Marburg, Marburg, Germany
    Competing interests
    No competing interests declared.
  6. Annika Schuermann

    University of Muenster, Muenster, Germany
    Competing interests
    No competing interests declared.
  7. Stefan Baumeister

    Faculty of Biology, Philipps-University Marburg, Marburg, Germany
    Competing interests
    No competing interests declared.
  8. Hyouk-Bum Kwon

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  9. Hans-Martin Maischein

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  10. Michael Potente

    Angiogenesis and Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    No competing interests declared.
  11. Wiebke Herzog

    University of Muenster, Muenster, Germany
    Competing interests
    No competing interests declared.
  12. Didier YR Stainier

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    For correspondence
    Didier.Stainier@mpi-bn.mpg.de
    Competing interests
    Didier YR Stainier, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0382-0026

Funding

Deutsche Forschungsgemeinschaft (SFB 834)

  • Didier YR Stainier

North Rhine-Westphalia (return fellowship')

  • Wiebke Herzog

Deutsche Forschungsgemeinschaft (SFB 834)

  • Christian SM Helker

Deutsche Forschungsgemeinschaft (GRK2213)

  • Christian SM Helker

Deutsche Forschungsgemeinschaft (GRK2213)

  • Jean Eberlein

Deutsche Forschungsgemeinschaft (GRK2213)

  • Julian Malchow

Deutsche Forschungsgemeinschaft (HE4585/3-1)

  • Wiebke Herzog

H2020 European Research Council (EMERGE (773047))

  • Michael Potente

Deutsche Forschungsgemeinschaft (EXC 2026)

  • Michael Potente

H2020 European Research Council (AdG project: ZMOD 694455)

  • Didier YR Stainier

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

Ethics

Animal experimentation: Ethics StatementAll zebrafish husbandry was performed under standard conditions, and all experiments were conducted in accordance with institutional (MPG) and national ethical and animal welfare guidelines (Proposal numbers: B2/1017, B2/1041, B2/1218, B2/1138). All procedures conform to the guidelines from Directive 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes.

Reviewing Editor

  1. Caroline E Burns, Boston Children's Hospital, United States

Publication history

  1. Received: January 29, 2020
  2. Accepted: September 19, 2020
  3. Accepted Manuscript published: September 21, 2020 (version 1)
  4. Version of Record published: October 16, 2020 (version 2)

Copyright

© 2020, Helker 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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