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PTPRG is an ischemia risk locus essential for HCO3--dependent regulation of endothelial function and tissue perfusion

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Cite this article as: eLife 2020;9:e57553 doi: 10.7554/eLife.57553

Abstract

Acid-base conditions modify artery tone and tissue perfusion but the involved vascular sensing mechanisms and disease consequences remain unclear. We experimentally investigated transgenic mice and performed genetic studies in a UK-based human cohort. We show that endothelial cells express the putative HCO3-sensor receptor-type tyrosine-protein phosphatase RPTPg, which enhances endothelial intracellular Ca2+-responses in resistance arteries and facilitates endothelium-dependent vasorelaxation only when CO2/HCO3 is present. Consistent with waning RPTPg-dependent vasorelaxation at low [HCO3], RPTPg limits increases in cerebral perfusion during neuronal activity and augments decreases in cerebral perfusion during hyperventilation. RPTPg does not influence resting blood pressure but amplifies hyperventilation-induced blood pressure elevations. Loss-of-function variants in PTPRG, encoding RPTPg, are associated with increased risk of cerebral infarction, heart attack, and reduced cardiac ejection fraction. We conclude that PTPRG is an ischemia susceptibility locus; and RPTPg-dependent sensing of HCO3 adjusts endothelium-mediated vasorelaxation, microvascular perfusion, and blood pressure during acid-base disturbances and altered tissue metabolism.

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Author details

  1. Kristoffer B Hansen

    Department of Biomedicine, Aarhus University, Aarhus C, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  2. Christian Staehr

    Department of Biomedicine, Aarhus University, Aarhus C, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  3. Palle D Rohde

    Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4347-8656
  4. Casper Homilius

    Department of Biomedicine, Aarhus University, Aarhus C, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  5. Sukhan Kim

    Department of Biomedicine, Aarhus University, Aarhus C, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  6. Mette Nyegaard

    Department of Biomedicine, Aarhus University, Aarhus C, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  7. Vladimir V Matchkov

    Department of Biomedicine, Aarhus University, Aarhus, Denmark
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3303-1095
  8. Ebbe Boedtkjer

    Department of Biomedicine, Aarhus University, Aarhus C, Denmark
    For correspondence
    eb@biomed.au.dk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5078-9279

Funding

Det Frie Forskningsråd (4183-00258B)

  • Ebbe Boedtkjer

Det Frie Forskningsråd (7025-00050A)

  • Ebbe Boedtkjer

Lundbeckfonden (R93-A8859)

  • Ebbe Boedtkjer

Lundbeckfonden (R287-2018-735)

  • Palle D Rohde

MEMBRANES Research Center

  • Ebbe Boedtkjer

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 accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Protocols were approved by the Danish Animal Experiments Inspectorate (2016-15-0201-00982). All surgery was performed under general anesthesia, and every effort was made to minimize suffering.

Human subjects: The research based on the UK Biobank resource was conducted under Application Number 60032

Reviewing Editor

  1. Arduino A Mangoni, Flinders Medical Centre, Australia

Publication history

  1. Received: April 3, 2020
  2. Accepted: September 18, 2020
  3. Accepted Manuscript published: September 21, 2020 (version 1)
  4. Version of Record published: October 7, 2020 (version 2)

Copyright

© 2020, Hansen 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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