PTPRG is an ischemia risk locus essential for HCO3–-dependent regulation of endothelial function and tissue perfusion

Abstract

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.

Phenylephrine-Induced Cardiovascular Changes in the Anesthetized Mouse: An Integrated Assessment of in vivo Hemodynamics Under Conditions of Controlled Heart Rate

“…Tidal volume was kept constant at 10 μl/g body mass ( Hauber et al, 2010 ). Ventilation rate was adjusted based on % etCO 2 at approximately 3.5% ( Hansen et al, 2020 ). Next, pancuronium-bromide (0.4 mg/h i.p., P1918, Sigma, United States), an M 2 -acetylcholine receptor blocker, was used to immobilize the mouse for the rest of protocol duration ( Uhlirova et al, 2016 ), and 0.9% NaCl solution (1 ml i.p., 9 mg/ml NaCl, Fresenius Kabi, Germany) was provided to balance out any fluid loss.…”

The Role of the Tumor Suppressor Gene Protein Tyrosine Phosphatase Gamma in Cancer

“…The first specific functional data obtained from murine embryonic stem cells described a role in the differentiation of the hematopoietic compartment ( Sorio et al, 1997 ), despite further analysis on another Ptprg -null mice model exhibited mild behavioral abnormalities without showing an obvious phenotype ( Lamprianou et al, 2006 ; Zhang et al, 2012 ). A role in the regulation of blood flow/pressure and in vascular relaxation through intracellular Ca 2+ response was described using the same murine model: under conditions of altered acid/base balance, such as low concentrations of [HCO 3- ], PTPRG-induced vasorelaxant effects, that were reduced in Ptprg -null mice ( Boedtkjer et al, 2016 ; Hansen et al, 2020 ). Moreover, a similar process was described the proximal renal tubules, where the presence of PTPRG increased the reabsorption of HCO 3- ( Zhou Y. et al, 2016 ).…”

Positive selection in the genomes of two Papua New Guinean populations at distinct altitude levels

“…This axis of the HIF pathway might maintain oxygen transport to appropriate levels in PNG highlanders while limiting the increase in haemoglobin concentration and blood viscosity. Moreover, five of the ten regions with the highest Fisher score include a gene associated with cardiovascular phenotypes (FBLN1 62 , GLT8D2 68 , DLGAP1 69 , PTPRG 70 and SLC24A4 71 ). This observation supports our hypothesis that selection in PNG highlanders acted on genes that might have helped them to counteract the hypoxic condition of their environment.…”