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Endothelial Ca2+ oscillations reflect VEGFR signaling-regulated angiogenic capacity in vivo

  1. Yasuhiro Yokota
  2. Hiroyuki Nakajima
  3. Yuki Wakayama
  4. Akira Muto
  5. Koichi Kawakami
  6. Shigetomo Fukuhara
  7. Naoki Mochizuki  Is a corresponding author
  1. National Cerebral and Cardiovascular Cener, Japan
  2. National Cerebral and Cardiovascular Center, Japan
  3. Graduate University for Advanced Studies, Japan
  4. National Institute of Genetics,, Japan
Research Article
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Cite this article as: eLife 2015;4:e08817 doi: 10.7554/eLife.08817

Abstract

Sprouting angiogenesis is a well-coordinated process controlled by multiple extracellular inputs, including vascular endothelial growth factor (VEGF). However, little is known about when and how individual endothelial cell (EC) responds to angiogenic inputs in vivo. Here, we visualized endothelial Ca2+ dynamics in zebrafish and found that intracellular Ca2+ oscillations occurred in ECs exhibiting angiogenic behavior. Ca2+ oscillations depended upon Vegfr2 and Vegfr3 in ECs budding from the dorsal aorta (DA) and posterior cardinal vein, respectively. Thus, visualizing Ca2+ oscillations allowed us to monitor EC responses to angiogenic cues. Vegfr-dependent Ca2+ oscillations occurred in migrating tip cells as well as stalk cells budding from the DA. We investigated how Dll4/Notch signaling regulates endothelial Ca2+ oscillations and found that it was required for the selection of single stalk cell as well as tip cell. Thus, we captured spatio-temporal Ca2+ dynamics during sprouting angiogenesis, as a result of cellular responses to angiogenic inputs.

Article and author information

Author details

  1. Yasuhiro Yokota

    Department of Cell Biology, National Cerebral and Cardiovascular Cener, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
  2. Hiroyuki Nakajima

    Department of Cell Biology, National Cerebral and Cardiovascular Center, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Yuki Wakayama

    Department of Cell Biology, National Cerebral and Cardiovascular Center, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Akira Muto

    Division of Molecular and Developmental Biology, National Institute of Genetics, Department of Genetics, Graduate University for Advanced Studies, Mishima, Japan
    Competing interests
    The authors declare that no competing interests exist.
  5. Koichi Kawakami

    Division of Molecular and Developmental Biology, National Institute of Genetics, Department of Genetics, National Institute of Genetics,, Mishima, Japan
    Competing interests
    The authors declare that no competing interests exist.
  6. Shigetomo Fukuhara

    Department of Cell Biology, National Cerebral and Cardiovascular Center, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
  7. Naoki Mochizuki

    Department of Cell Biology, National Cerebral and Cardiovascular Center, Suita, Japan
    For correspondence
    nmochizu@ri.ncvc.go.jp
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: Animal experimentation: The experiments using zebrafish were approved by the animal committee of National Cerebral and Cardiovascular Center (No. 14005) and performed according to the guidance of the Institute.

Reviewing Editor

  1. Janet Rossant, University of Toronto, Canada

Publication history

  1. Received: May 18, 2015
  2. Accepted: November 19, 2015
  3. Accepted Manuscript published: November 20, 2015 (version 1)
  4. Version of Record published: December 31, 2015 (version 2)

Copyright

© 2015, Yokota 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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