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

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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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All data generated or analysed during this study are presented in the manuscript

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Kristoffer B Hansen

Department of Biomedicine, Aarhus University, Aarhus C, Denmark

Competing interests
The authors declare that no competing interests exist.
Christian Staehr

Department of Biomedicine, Aarhus University, Aarhus C, Denmark

Competing interests
The authors declare that no competing interests exist.
Palle D Rohde

Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4347-8656
Casper Homilius

Department of Biomedicine, Aarhus University, Aarhus C, Denmark

Competing interests
The authors declare that no competing interests exist.
Sukhan Kim

Department of Biomedicine, Aarhus University, Aarhus C, Denmark

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The authors declare that no competing interests exist.
Mette Nyegaard

Department of Biomedicine, Aarhus University, Aarhus C, Denmark

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The authors declare that no competing interests exist.
Vladimir V Matchkov

Department of Biomedicine, Aarhus University, Aarhus, Denmark

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3303-1095
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.

"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

Copyright

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.