1. Developmental Biology
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VE-cadherin enables trophoblast endovascular invasion and spiral artery remodeling during placental development

  1. Derek C Sung
  2. Xiaowen Chen
  3. Mei Chen
  4. Jisheng Yang
  5. Susan Schultz
  6. Apoorva Babu
  7. Yitian Xu
  8. Siqi Gao
  9. Thomas C Stevenson Keller
  10. Patricia Mericko
  11. Michelle Lee
  12. Ying Yang
  13. Joshua P Scallan
  14. Mark L Kahn  Is a corresponding author
  1. University of Pennsylvania, United States
  2. University of South Florida, United States
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Cite this article as: eLife 2022;11:e77241 doi: 10.7554/eLife.77241

Abstract

During formation of the mammalian placenta trophoblasts invade the maternal decidua and remodel spiral arteries to bring maternal blood into the placenta. This process, known as endovascular invasion, is thought to involve the adoption of functional characteristics of vascular endothelial cells (ECs) by trophoblasts. The genetic and molecular basis of endovascular invasion remains poorly defined, however, and whether trophoblasts utilize specialized endothelial proteins in an analogous manner to create vascular channels remains untested. Vascular endothelial (VE-)cadherin is a homotypic adhesion protein that is expressed selectively by ECs in which it enables formation of tight vessels and regulation of EC junctions. VE-cadherin is also expressed in invasive trophoblasts and is a prime candidate for a molecular mechanism of endovascular invasion by those cells. Here, we show that the VE-cadherin is required for trophoblast migration and endovascular invasion into the maternal decidua in the mouse. VE-cadherin deficiency results in loss of spiral artery remodeling that leads to decreased flow of maternal blood into the placenta, fetal growth restriction, and death. These studies identify a non-endothelial role for VE-cadherin in trophoblasts during placental development and suggest that endothelial proteins may play functionally unique roles in trophoblasts that do not simply mimic those in ECs.

Data availability

Source Data files have been included for Figure 1, Figure 1-Supplemental Figure 1, Figure 1-Supplemental Figure 2, Figure 1-Supplemental Figure 3, Figure 2, Figure 3, Figure 4-Supplemental Figure 1, and Figure 4-Supplemental Figure 2. All reagents have been listed in the Methods section in this paper.The RNA-seq data set has been deposited in the NCBI GEO under accession ID number GSE189408. Investigators interested in the animals used in this study should contact Dr. Jeremy Veenstra-Vanderweele (Columbia University), Dr. Gustsavo Leone (Medical University of South Carolina), and Dr. Joshua Scallan (University of South Florida).

The following data sets were generated

Article and author information

Author details

  1. Derek C Sung

    Department of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6966-2596
  2. Xiaowen Chen

    Department of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Mei Chen

    Department of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jisheng Yang

    Department of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Susan Schultz

    Department of Radiology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Apoorva Babu

    Department of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Yitian Xu

    Department of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Siqi Gao

    Department of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Thomas C Stevenson Keller

    Department of Radiology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Patricia Mericko

    Department of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Michelle Lee

    University Laboratory Animal Resources, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Ying Yang

    Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Joshua P Scallan

    Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Mark L Kahn

    University Laboratory Animal Resources, University of Pennsylvania, Philadelphia, United States
    For correspondence
    markkahn@pennmedicine.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6489-7086

Funding

National Institutes of Health (T32 HL007439)

  • Derek C Sung

National Institutes of Health (F30 HL158014)

  • Derek C Sung

American Heart Association (Postdoctoral Fellowship 35200213)

  • Xiaowen Chen

National Institutes of Health (T32 HL007971)

  • Thomas C Stevenson Keller

American Heart Association (Postdoctoral fellowship 836238)

  • Thomas C Stevenson Keller

National Institutes of Health (HL142905)

  • Joshua P Scallan

National Institutes of Health (HL145397)

  • Ying Yang

National Institutes of Health (HL142976)

  • Mark L Kahn

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

Ethics

Animal experimentation: All procedures were conducted using an approved animal protocol (806811) in accordance with the University of Pennsylvania Institutional Animal Care and Use Committee.

Reviewing Editor

  1. Gou Young Koh, Institute of Basic Science and Korea Advanced Institute of Science and Technology (KAIST), Korea (South), Republic of

Publication history

  1. Received: January 21, 2022
  2. Preprint posted: February 16, 2022 (view preprint)
  3. Accepted: April 28, 2022
  4. Accepted Manuscript published: April 29, 2022 (version 1)
  5. Version of Record published: May 13, 2022 (version 2)

Copyright

© 2022, Sung 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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