VEGF-A regulated by progesterone governs uterine angiogenesis and vascular remodelling during pregnancy

Authors

  • Minah Kim,

    1. Laboratory of Vascular Biology and Stem Cells and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
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    • These authors contributed equally to this work.
  • Hyeung Ju Park,

    1. Laboratory of Vascular Biology and Stem Cells and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
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    • These authors contributed equally to this work.
  • Jae Won Seol,

    1. Laboratory of Vascular Biology and Stem Cells and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
    2. College of Veterinary Medicine, Chonbuk National University, Jeonju, Korea
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    • These authors contributed equally to this work.
  • Jeon Yeob Jang,

    1. Laboratory of Vascular Biology and Stem Cells and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
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  • Young-Suk Cho,

    1. Laboratory of Vascular Biology and Stem Cells and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
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  • Kyu Rae Kim,

    1. Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
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  • Youngsok Choi,

    1. Department of Biomedical Science, CHA University, Seoul, Korea
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  • John P. Lydon,

    1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
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  • Francesco J. DeMayo,

    1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
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  • Masabumi Shibuya,

    1. Institute of Physiology and Medicine, Jobu University, Gunma, Japan
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  • Napoleone Ferrara,

    1. Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
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  • Hoon-Ki Sung,

    1. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
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  • Andras Nagy,

    1. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
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  • Kari Alitalo,

    1. Molecular/Cancer Biology Laboratory, Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
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  • Gou Young Koh

    Corresponding author
    1. Laboratory of Vascular Biology and Stem Cells and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
    • Corresponding author: Tel: +82 42 350 2638; Fax: +82 42 350 2610;

      E-mail: gykoh@kaist.ac.kr

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Abstract

The features and regulation of uterine angiogenesis and vascular remodelling during pregnancy are poorly defined. Here we show that dynamic and variable decidual angiogenesis (sprouting, intussusception and networking), and active vigorous vascular remodelling such as enlargement and elongation of ‘vascular sinus folding’ (VSF) and mural cell drop-out occur distinctly in a spatiotemporal manner in the rapidly growing mouse uterus during early pregnancy — just after implantation but before placentation. Decidual angiogenesis is mainly regulated through VEGF-A secreted from the progesterone receptor (PR)-expressing decidual stromal cells which are largely distributed in the anti-mesometrial region (AMR). In comparison, P4-PR-regulated VEGF-A-VEGFR2 signalling, ligand-independent VEGFR3 signalling and uterine natural killer (uNK) cells positively and coordinately regulate enlargement and elongation of VSF. During the postpartum period, Tie2 signalling could be involved in vascular maturation at the endometrium in a ligand-independent manner, with marked reduction of VEGF-A, VEGFR2 and PR expressions. Overall, we show that two key vascular growth factor receptors — VEGFR2 and Tie2 — strikingly but differentially regulate decidual angiogenesis and vascular remodelling in rapidly growing and regressing uteri in an organotypic manner.

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