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

Author:

Hansen Kristoffer B1,Staehr Christian1,Rohde Palle D2ORCID,Homilius Casper1,Kim Sukhan1,Nyegaard Mette1,Matchkov Vladimir V1ORCID,Boedtkjer Ebbe1ORCID

Affiliation:

1. Department of Biomedicine, Aarhus University, Aarhus, Denmark

2. Department of Chemistry and Bioscience, Aalborg University, Aalborg, 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 RPTPγ, which enhances endothelial intracellular Ca2+-responses in resistance arteries and facilitates endothelium-dependent vasorelaxation only when CO2/HCO3 is present. Consistent with waning RPTPγ-dependent vasorelaxation at low [HCO3], RPTPγ limits increases in cerebral perfusion during neuronal activity and augments decreases in cerebral perfusion during hyperventilation. RPTPγ does not influence resting blood pressure but amplifies hyperventilation-induced blood pressure elevations. Loss-of-function variants in PTPRG, encoding RPTPγ, 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 RPTPγ-dependent sensing of HCO3 adjusts endothelium-mediated vasorelaxation, microvascular perfusion, and blood pressure during acid-base disturbances and altered tissue metabolism.

Funder

Det Frie Forskningsråd

Lundbeckfonden

MEMBRANES Research Center

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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