PTPRG is an ischemia risk locus essential for HCO3--dependent regulation of endothelial function and tissue perfusion
- Aarhus University, Denmark
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.
Data availability
All data generated or analysed during this study are presented in the manuscript
Article and author information
Author details
Vladimir V Matchkov
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
© 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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PTPRG is an ischemia risk locus essential for HCO3--dependent regulation of endothelial function and tissue perfusion
eLife 9:e57553.
https://doi.org/10.7554/eLife.57553
