1. Developmental Biology
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Angiopoietin receptor Tie2 is required for vein specification and maintenance via regulating COUP-TFII

  1. Man Chu
  2. Taotao Li
  3. Bin Shen
  4. Xudong Cao
  5. Haoyu Zhong
  6. Luqing Zhang
  7. Fei Zhou
  8. Wenjuan Ma
  9. Haijuan Jiang
  10. Pancheng Xie
  11. Zhengzheng Liu
  12. Ningzheng Dong
  13. Ying Xu
  14. Yun Zhao
  15. Guoqiang Xu
  16. Peirong Lu
  17. Jincai Luo
  18. Qingyu Wu
  19. Kari Alitalo
  20. Gou Young Koh
  21. Ralf H Adams
  22. Yulong He  Is a corresponding author
  1. Soochow University, China
  2. Peking University, China
  3. University of Helsinki, Finland
  4. Institute of Basic Science and Korea Advanced Institute of Science and Technology, Republic of Korea
  5. Max-Planck-Institute for Molecular Biomedicine, Germany
Research Article
  • Cited 14
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Cite this article as: eLife 2016;5:e21032 doi: 10.7554/eLife.21032

Abstract

Mechanisms underlying the vein development remain largely unknown. Tie2 signaling mediates endothelial cell (EC) survival and vascular maturation and its activating mutations are linked to venous malformations. Here we show that vein formation are disrupted in mouse skin and mesentery when Tie2 signals are diminished by targeted deletion of Tek either ubiquitously or specifically in embryonic ECs. Postnatal Tie2 attenuation resulted in the degeneration of newly formed veins followed by the formation of haemangioma-like vascular tufts in retina and venous tortuosity. Mechanistically, Tie2 insufficiency compromised venous EC identity, as indicated by a significant decrease of COUP-TFII protein level, a key regulator in venogenesis. Consistently, angiopoietin-1 stimulation increased COUP-TFII in cultured ECs, while Tie2 knockdown or blockade of Tie2 downstream PI3K/Akt pathway reduced COUP-TFII which could be reverted by the proteasome inhibition. Together, our results imply that Tie2 is essential for venous specification and maintenance via Akt mediated stabilization of COUP-TFII.

Article and author information

Author details

  1. Man Chu

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
  2. Taotao Li

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
  3. Bin Shen

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
  4. Xudong Cao

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
  5. Haoyu Zhong

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
  6. Luqing Zhang

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
  7. Fei Zhou

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1857-8831
  8. Wenjuan Ma

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
  9. Haijuan Jiang

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
  10. Pancheng Xie

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
  11. Zhengzheng Liu

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
  12. Ningzheng Dong

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
  13. Ying Xu

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6689-7768
  14. Yun Zhao

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
  15. Guoqiang Xu

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
  16. Peirong Lu

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
  17. Jincai Luo

    Laboratory of Vascular Biology, Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    No competing interests declared.
  18. Qingyu Wu

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    Competing interests
    No competing interests declared.
  19. Kari Alitalo

    Wihuri Research Institute, University of Helsinki, Helsinki, Finland
    Competing interests
    Kari Alitalo, Reviewing editor, eLife.
  20. Gou Young Koh

    Center for Vascular Research, Institute of Basic Science and Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    No competing interests declared.
  21. Ralf H Adams

    Max-Planck-Institute for Molecular Biomedicine, Münster, Germany
    Competing interests
    No competing interests declared.
  22. Yulong He

    Cyrus Tang Hematology Center, Soochow University, Suzhou, China
    For correspondence
    yulong.he@mpi-muenster.mpg.de
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0099-3749

Funding

National Natural Science Foundation of China (91539101,31271530,31071263)

  • Yulong He

Ministry of Science and Technology of the People's Republic of China (2012CB947600)

  • Yulong He

Priority Program Development of Jiangsu Higher Education Institutions

  • Yulong He

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

Ethics

Animal experimentation: Conditional mice with Tek gene targeted flox sites for gene deletion were generated by the National Resource Center for Mutant Mice, Nanjing University. All animal experiments were performed in accordance with the institutional guidelines of the Soochow and Nanjing University Animal Center (MARC-AP#YH2).

Reviewing Editor

  1. Elisabetta Dejana, FIRC Institute of Molecular Oncology, Italy

Publication history

  1. Received: August 28, 2016
  2. Accepted: December 21, 2016
  3. Accepted Manuscript published: December 22, 2016 (version 1)
  4. Version of Record published: January 6, 2017 (version 2)

Copyright

© 2016, Chu 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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