Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Department of Chemistry and Bioscience, Aalborg University, Aalborg, Denmark.
Elife. 2020 Sep 21;9:e57553. doi: 10.7554/eLife.57553.
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-sensor receptor-type tyrosine-protein phosphatase RPTPγ, which enhances endothelial intracellular Ca-responses in resistance arteries and facilitates endothelium-dependent vasorelaxation only when CO/HCO is present. Consistent with waning RPTPγ-dependent vasorelaxation at low [HCO], 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 , encoding RPTPγ, are associated with increased risk of cerebral infarction, heart attack, and reduced cardiac ejection fraction. We conclude that is an ischemia susceptibility locus; and RPTPγ-dependent sensing of HCO adjusts endothelium-mediated vasorelaxation, microvascular perfusion, and blood pressure during acid-base disturbances and altered tissue metabolism.
酸碱条件会改变动脉张力和组织灌注，但涉及的血管感应机制和疾病后果仍不清楚。我们通过实验研究了转基因小鼠，并在一个基于英国的人类队列中进行了遗传研究。我们表明内皮细胞表达假定的 HCO 感应受体型酪氨酸蛋白磷酸酶 RPTPγ，当 CO/HCO 存在时，它增强阻力血管中的内皮细胞内 Ca 反应，并促进内皮依赖性血管舒张。与低 [HCO] 时 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，并增加过度通气期间脑灌注的减少。RPTPγ 不影响静息血压，但会放大过度通气引起的血压升高。编码 RPTPγ 的 中的功能丧失变体与脑梗死、心脏病发作和射血分数降低的风险增加相关。我们得出结论， 是缺血易感性位点；并且 RPTPγ 依赖性的 HCO 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。
