Synchronization of endothelial Dll4-Notch dynamics switch blood vessels from branching to expansion

  1. Benedetta Ubezio
  2. Raquel Agudo Blanco
  3. Ilse Geudens
  4. Fabio Stanchi
  5. Thomas Mathivet
  6. Martin L Jones
  7. Anan Ragab
  8. Katie Bentley
  9. Holger Gerhardt  Is a corresponding author
  1. London Research Institute, United Kingdom
  2. Vesalius Research Center, VIB, Belgium
  3. Harvard Medical School, United States

Abstract

Formation of a regularly branched blood vessel network is crucial in development and physiology. Here we show that the expression of the Notch ligand Dll4 fluctuates in individual endothelial cells within sprouting vessels in the mouse retina in vivo and in correlation with dynamic cell movement in mouse embryonic stem cell-derived sprouting assays. We also find that sprout elongation and branching associates with a highly differential phase pattern of Dll4 between endothelial cells. Stimulation with pathologically high levels of Vegf, or overexpression of Dll4, leads to Notch dependent synchronization of Dll4 fluctuations within clusters, both in vitro and in vivo. Our results demonstrate that the Vegf-Dll4/Notch feedback system normally operates to generate heterogeneity between endothelial cells driving branching, whilst synchronization drives vessel expansion. We propose that this sensitive phase transition in the behaviour of the Vegf-Dll4/Notch feedback loop underlies the morphogen function of Vegfa in vascular patterning.

Article and author information

Author details

  1. Benedetta Ubezio

    Vascular Biology Laboratory, London Research Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Raquel Agudo Blanco

    Vascular Biology Laboratory, London Research Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Ilse Geudens

    Vascular Patterning Laboratory, Vesalius Research Center, VIB, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  4. Fabio Stanchi

    Vascular Patterning Laboratory, Vesalius Research Center, VIB, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  5. Thomas Mathivet

    Vascular Patterning Laboratory, Vesalius Research Center, VIB, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  6. Martin L Jones

    Vascular Biology Laboratory, London Research Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Anan Ragab

    Vascular Biology Laboratory, London Research Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Katie Bentley

    Computational Biology Laboratory, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Holger Gerhardt

    Vascular Biology Laboratory, London Research Institute, London, United Kingdom
    For correspondence
    holger.gerhardt@mdc-berlin.de
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Tanya T Whitfield, University of Sheffield, United Kingdom

Ethics

Animal experimentation: Mice were maintained at London Research Institute under standard husbandry conditions. All protocols were approved by the UK Home Office (P80/2391). Glioblastoma studies were performed at the Vesalius Research Center, VIB, KU Leuven where housing and all experimental animal procedures were performed in accordance with Belgian law on animal care and were approved by the Institutional Animal Care and Research Advisory Committee of the K. U. Leuven (P105/2012).

Version history

  1. Received: October 7, 2015
  2. Accepted: April 11, 2016
  3. Accepted Manuscript published: April 13, 2016 (version 1)
  4. Version of Record published: June 6, 2016 (version 2)
  5. Version of Record updated: May 9, 2017 (version 3)

Copyright

© 2016, Ubezio 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.

Metrics

  • 4,797
    views
  • 1,290
    downloads
  • 101
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Benedetta Ubezio
  2. Raquel Agudo Blanco
  3. Ilse Geudens
  4. Fabio Stanchi
  5. Thomas Mathivet
  6. Martin L Jones
  7. Anan Ragab
  8. Katie Bentley
  9. Holger Gerhardt
(2016)
Synchronization of endothelial Dll4-Notch dynamics switch blood vessels from branching to expansion
eLife 5:e12167.
https://doi.org/10.7554/eLife.12167

Share this article

https://doi.org/10.7554/eLife.12167

Further reading

    1. Computational and Systems Biology
    2. Neuroscience
    Sara Ibañez, Nilapratim Sengupta ... Christina M Weaver
    Research Article

    Normal aging leads to myelin alterations in the rhesus monkey dorsolateral prefrontal cortex (dlPFC), which are positively correlated with degree of cognitive impairment. It is hypothesized that remyelination with shorter and thinner myelin sheaths partially compensates for myelin degradation, but computational modeling has not yet explored these two phenomena together systematically. Here, we used a two-pronged modeling approach to determine how age-related myelin changes affect a core cognitive function: spatial working memory. First, we built a multicompartment pyramidal neuron model fit to monkey dlPFC empirical data, with an axon including myelinated segments having paranodes, juxtaparanodes, internodes, and tight junctions. This model was used to quantify conduction velocity (CV) changes and action potential (AP) failures after demyelination and subsequent remyelination. Next, we incorporated the single neuron results into a spiking neural network model of working memory. While complete remyelination nearly recovered axonal transmission and network function to unperturbed levels, our models predict that biologically plausible levels of myelin dystrophy, if uncompensated by other factors, can account for substantial working memory impairment with aging. The present computational study unites empirical data from ultrastructure up to behavior during normal aging, and has broader implications for many demyelinating conditions, such as multiple sclerosis or schizophrenia.

    1. Computational and Systems Biology
    2. Neuroscience
    Andrea I Luppi, Pedro AM Mediano ... Emmanuel A Stamatakis
    Research Article

    How is the information-processing architecture of the human brain organised, and how does its organisation support consciousness? Here, we combine network science and a rigorous information-theoretic notion of synergy to delineate a ‘synergistic global workspace’, comprising gateway regions that gather synergistic information from specialised modules across the human brain. This information is then integrated within the workspace and widely distributed via broadcaster regions. Through functional MRI analysis, we show that gateway regions of the synergistic workspace correspond to the human brain’s default mode network, whereas broadcasters coincide with the executive control network. We find that loss of consciousness due to general anaesthesia or disorders of consciousness corresponds to diminished ability of the synergistic workspace to integrate information, which is restored upon recovery. Thus, loss of consciousness coincides with a breakdown of information integration within the synergistic workspace of the human brain. This work contributes to conceptual and empirical reconciliation between two prominent scientific theories of consciousness, the Global Neuronal Workspace and Integrated Information Theory, while also advancing our understanding of how the human brain supports consciousness through the synergistic integration of information.