PTPRG is an ischemia risk locus essential for HCO.sub.3.sup.---dependent regulation of endothelial function and tissue perfusion

• Published in: eLife Vol. 9
• Main Authors: Hansen, Kristoffer B, Staehr, Christian, Rohde, Palle D, Homilius, Casper, Kim, Sukhan, Nyegaard, Mette, Matchkov, Vladimir V, Boedtkjer, Ebbe
• Format: Journal Article
• Language: English
• Published: eLife Science Publications, Ltd 21-09-2020
• Subjects: Carbonates; Disease susceptibility; Endothelium; Genetic engineering; Ischemia; Phosphatases; Physiological aspects; Protein binding; Proteins; Sensors; Tyrosine
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.57553

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 HCO.sub.3.sup.---sensor receptor-type tyrosine-protein phosphatase RPTP[gamma], which enhances endothelial intracellular Ca.sup.2+-responses in resistance arteries and facilitates endothelium-dependent vasorelaxation only when CO.sub.2/HCO.sub.3.sup.-- is present. Consistent with waning RPTP[gamma]-dependent vasorelaxation at low [HCO.sub.3.sup.--], RPTP[gamma] limits increases in cerebral perfusion during neuronal activity and augments decreases in cerebral perfusion during hyperventilation. RPTP[gamma] does not influence resting blood pressure but amplifies hyperventilation-induced blood pressure elevations. Loss-of-function variants in PTPRG, encoding RPTP[gamma], 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 RPTP[gamma]-dependent sensing of HCO.sub.3.sup.-- adjusts endothelium-mediated vasorelaxation, microvascular perfusion, and blood pressure during acid-base disturbances and altered tissue metabolism.