PTPRG is an ischemia risk locus essential for HCO 3 - -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 putative HCO3 - -sensor receptor-type tyrosine-protein phosphatase RPTPg, which enhances endothelial intracellular Ca2+ -responses in resistance arteries and facilitates endothelium-dependent vasorelaxation only when CO2 /HCO3 - is present. Consistent with waning RPTPg-dependent vasorelaxation at low [HCO3 - ], RPTPg limits increases in cerebral perfusion during neuronal activity and augments decreases in cerebral perfusion during hyperventilation. RPTPg does not influence resting blood pressure but amplifies hyperventilation-induced blood pressure elevations. Loss-of-function variants in PTPRG , encoding RPTPg, 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 RPTPg-dependent sensing of HCO3 - adjusts endothelium-mediated vasorelaxation, microvascular perfusion, and blood pressure during acid-base disturbances and altered tissue metabolism.