1. Computational and Systems Biology
  2. Developmental Biology
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Vascular dimorphism ensured by regulated proteoglycan dynamics favors rapid umbilical artery closure at birth

  1. Sumeda Nandadasa
  2. Jason M Szafron
  3. Vai Pathak
  4. Sae-Il Murtada
  5. Caroline M Kraft
  6. Anna O'Donnell
  7. Christian Norvik
  8. Clare Hughes
  9. Bruce Caterson
  10. Miriam S Domowicz
  11. Nancy B Schwartz
  12. Karin Tran-Lundmark
  13. Martina Veigl
  14. David Sedwick
  15. Elliot H Philipson
  16. Jay D Humphrey  Is a corresponding author
  17. Suneel S Apte  Is a corresponding author
  1. Cleveland Clinic Lerner Research Institute, United States
  2. Yale University, United States
  3. Case Western Reserve University, United States
  4. Yale University School of Engineering and Applied Science, United States
  5. Lund University, Sweden
  6. Cardiff University, United Kingdom
  7. University of Chicago, United States
  8. Cleveland Clinic, United States
Research Article
  • Cited 3
  • Views 924
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Cite this article as: eLife 2020;9:e60683 doi: 10.7554/eLife.60683

Abstract

The umbilical artery lumen closes rapidly at birth, preventing neonatal blood loss, whereas the umbilical vein remains patent longer. Here, analysis of umbilical cords from humans and other mammals identified differential arterial-venous proteoglycan dynamics as a determinant of these contrasting vascular responses. The umbilical artery, but not the vein, has an inner layer enriched in the hydrated proteoglycan aggrecan, external to which lie contraction-primed smooth muscle cells (SMC). At birth, SMC contraction drives inner layer buckling and centripetal displacement to occlude the arterial lumen, a mechanism revealed by biomechanical observations and confirmed by computational analyses. This vascular dimorphism arises from spatially regulated proteoglycan expression and breakdown. Mice lacking aggrecan or the metalloprotease ADAMTS1, which degrades proteoglycans, demonstrate their opposing roles in umbilical vascular dimorphism, including effects on SMC differentiation. Umbilical vessel dimorphism is conserved in mammals, suggesting that differential proteoglycan dynamics and inner layer buckling were positively selected during evolution.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

The following data sets were generated

Article and author information

Author details

  1. Sumeda Nandadasa

    Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jason M Szafron

    Department of Biomedical Engineering, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9476-5175
  3. Vai Pathak

    Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sae-Il Murtada

    Department of Biomedical Engineering, Yale University School of Engineering and Applied Science, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Caroline M Kraft

    Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Anna O'Donnell

    Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Christian Norvik

    Department of Experimental Medical Science and Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  8. Clare Hughes

    School of Biosciences, Cardiff University, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4726-5877
  9. Bruce Caterson

    School of Biosciences, Cardiff University, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Miriam S Domowicz

    Department of Pediatrics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7860-4427
  11. Nancy B Schwartz

    Postdoctoral Affairs and Association, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Karin Tran-Lundmark

    Department of Experimental Medical Science and Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  13. Martina Veigl

    Department of Medicine, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. David Sedwick

    Department of Medicine, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Elliot H Philipson

    The Women's Health Institute, Department of Obstetrics and Gynecology, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Jay D Humphrey

    Department of Biomedical Engineering, Yale University School of Engineering and Applied Science, New Haven, United States
    For correspondence
    jay.humphrey@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
  17. Suneel S Apte

    Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, United States
    For correspondence
    aptes@ccf.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8441-1226

Funding

National Institutes of Health (HL107147)

  • Suneel S Apte

National Institutes of Health (HL141130)

  • Suneel S Apte

American Heart Association (17DIA33820024)

  • Suneel S Apte

Sabrina's Foundation (None)

  • Elliot H Philipson

National Children's Study (Formative Research Project L01-3-RT-01-E,Contract # HHSN272500800009C)

  • Martina Veigl
  • David Sedwick

Mark Lauer Pediatric Research Grant (None)

  • Sumeda Nandadasa

National Institutes of Health (CA43703)

  • Martina Veigl

Swedish Heart-Lung Foundation (None)

  • Karin Tran-Lundmark

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols: 18-1996 and 18-2045 (Cleveland Clinic IACUC), 2018-11508 (Yale University IACUC) and 43751 (University of Chicago IACUC).

Human subjects: Human umbilical cord samples were collected under an IRB exemption (EX-0118) from Cleveland Clinic for use of discarded tissue without patient identifiers. These cords were used for histological/immunohistologic analysis, in situ hybridization, and transcriptomics of inner vs outer umbilical artery TM. For microarray analysis of umbilical cord artery versus vein, human umbilical cords were collected separately through the National Children's Study under University Hospitals-Case Medical Center approved IRB protocol 01-11-28.

Reviewing Editor

  1. Karen Downs, University of Wisconsin-Madison School of Medicine and Public Health, United States

Publication history

  1. Received: July 2, 2020
  2. Accepted: September 9, 2020
  3. Accepted Manuscript published: September 10, 2020 (version 1)
  4. Version of Record published: October 1, 2020 (version 2)

Copyright

© 2020, Nandadasa 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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