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

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 putat...

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Bibliographic Details
Main Authors: Kristoffer B Hansen, Christian Staehr, Palle D Rohde, Casper Homilius, Sukhan Kim, Mette Nyegaard, Vladimir V Matchkov, Ebbe Boedtkjer
Format: Article
Language:English
Published: eLife Sciences Publications Ltd 2020-09-01
Series:eLife
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Online Access:https://elifesciences.org/articles/57553
Description
Summary: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.
ISSN:2050-084X