1. Computational and Systems Biology
  2. Developmental Biology
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Temporal modulation of collective cell behavior controls vascular network topology

  1. Esther Kur
  2. Jiha Kim
  3. Aleksandra Tata
  4. Cesar H Comin
  5. Kyle I Harrington
  6. Luciano da F Costa
  7. Katie Bentley
  8. Chenghua Gu  Is a corresponding author
  1. Harvard Medical School, United States
  2. University of Sao Paulo, Brazil
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Cite this article as: eLife 2016;5:e13212 doi: 10.7554/eLife.13212

Abstract

Vascular network density determines the amount of oxygen and nutrients delivered to host tissues, but how the vast diversity of densities is generated is unknown. Reiterations of endothelial-tip-cell selection, sprout extension and anastomosis are the basis for vascular network generation, a process governed by VEGF/Notch feedback loop. Here, we find that temporal regulation of this feedback loop, a previously unexplored dimension, is the key mechanism to determine vascular density. Iterating between computational modeling and in vivo live imaging, we demonstrate that the rate of tip-cell selection determines the length of linear sprout extension at the expense of branching, dictating network density. We provide the first example of a host tissue-derived signal (Semaphorin3E-Plexin-D1) that accelerates tip cell selection rate, yielding a dense network. We propose that temporal regulation of this critical, iterative aspect of network formation could be a general mechanism, and additional temporal regulators may exist to sculpt vascular topology.

Article and author information

Author details

  1. Esther Kur

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jiha Kim

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Aleksandra Tata

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Cesar H Comin

    Instituto de Física de São Carlos, University of Sao Paulo, Sao Carlos, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  5. Kyle I Harrington

    Department of Pathology, 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.
  6. Luciano da F Costa

    Instituto de Física de São Carlos, University of Sao Paulo, Sao Carlos, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  7. Katie Bentley

    Department of Pathology, 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.
  8. Chenghua Gu

    Department of Neurobiology, Harvard Medical School, Boston, United States
    For correspondence
    Chenghua_Gu@hms.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All animals were treated according to institutional and US National Institutes of Health (NIH) guidelines approved by the Institutional Animal Care and Use Committee (IACUC) protocols (# 04146) at Harvard Medical School.

Reviewing Editor

  1. Jeremy Nathans, Johns Hopkins University School of Medicine, United States

Publication history

  1. Received: November 20, 2015
  2. Accepted: February 23, 2016
  3. Accepted Manuscript published: February 24, 2016 (version 1)
  4. Version of Record published: March 22, 2016 (version 2)

Copyright

© 2016, Kur 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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