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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 3  – -sensor receptor-type tyrosine-protein phosphatase RPTPγ, which enhances endothelial intracellular Ca 2+ -responses in resistance arteries and facilitates endothelium-dependent vasorelaxation only when CO 2 /HCO 3  –  is present. Consistent with waning RPTPγ-dependent vasorelaxation at low [HCO 3  – ], 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 HCO 3  –  adjusts endothelium-mediated vasorelaxation, microvascular perfusion, and blood pressure during acid-base disturbances and altered tissue metabolism.

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