< i > PTPRG < /i > is an ischemia risk locus essential for HCO < sub > 3 < /sub > < sup > - < /sup > -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 inPTPRG, encoding RPTPg, are associated with increased risk of cerebral infarction, heart attack, and reduced cardiac ejection fraction. We conclude thatPTPRG 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.
Source: eLife - Category: Biomedical Science Tags: Genetics and Genomics Medicine Source Type: research