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.

中文翻译：

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PTPRG 是 HCO3 依赖性内皮功能和组织灌注调节必不可少的缺血风险位点

酸碱条件会改变动脉张力和组织灌注，但所涉及的血管感应机制和疾病后果仍不清楚。我们对转基因小鼠进行了实验研究，并在英国的一个人类队列中进行了遗传研究。我们显示内皮细胞表达假定的 HCO3--传感器受体型酪氨酸蛋白磷酸酶 RPTPγ，它增强阻力动脉中的内皮细胞内 Ca2+-反应，并仅在 CO2/HCO3- 存在时促进内皮依赖性血管舒张。与在低 [HCO3–] 下 RPTPγ 依赖性血管舒张减弱一致，RPTPγ 限制神经元活动期间脑灌注的增加，并增加过度换气期间脑灌注的减少。RPTPγ 不影响静息血压，但会放大过度换气引起的血压升高。PTPRG 中编码 RPTPγ 的功能丧失变体与脑梗塞、心脏病发作和心脏射血分数降低的风险增加有关。我们得出结论，PTPRG 是一个缺血易感位点；和 RPTPγ 依赖的 HCO3 感应在酸碱紊乱和组织代谢改变期间调节内皮介导的血管舒张、微血管灌注和血压。