TY - JOUR TI - PTPRG is an ischemia risk locus essential for HCO3–-dependent regulation of endothelial function and tissue perfusion AU - Hansen, Kristoffer B AU - Staehr, Christian AU - Rohde, Palle D AU - Homilius, Casper AU - Kim, Sukhan AU - Nyegaard, Mette AU - Matchkov, Vladimir V AU - Boedtkjer, Ebbe A2 - Mangoni, Arduino A A2 - Barton, Matthias A2 - Mangoni, Arduino A VL - 9 PY - 2020 DA - 2020/09/21 SP - e57553 C1 - eLife 2020;9:e57553 DO - 10.7554/eLife.57553 UR - https://doi.org/10.7554/eLife.57553 AB - 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. KW - acidosis KW - bicarbonate KW - cerebral blood flow and metabolism KW - endothelium-dependent vasorelaxation KW - metabolic regulation KW - ischemia JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -