A continuous supply of oxygen is essential for the survival of multicellular organisms. The understanding of how this supply is regulated in the microvasculature has evolved from viewing erythrocytes (red blood cells [RBCs]) as passive carriers of oxygen to recognizing the complex interplay between Hb (hemoglobin) and oxygen, carbon dioxide, and nitric oxide-the three-gas respiratory cycle-that insures adequate oxygen and nutrient delivery to meet local metabolic demand. In this context, it is blood flow and not blood oxygen content that is the main driver of tissue oxygenation by RBCs. Herein, we review the lines of experimentation that led to this understanding of RBC function; from the foundational understanding of allosteric regulation of oxygen binding in Hb in the stereochemical model of Perutz, to blood flow autoregulation (hypoxic vasodilation governing oxygen delivery) observed by Guyton, to current understanding that centers on S-nitrosylation of Hb (ie, S-nitrosohemoglobin; SNO-Hb) as a purveyor of oxygen-dependent vasodilatory activity. Notably, hypoxic vasodilation is recapitulated by native S-nitrosothiol (SNO)-replete RBCs and by SNO-Hb itself, whereby SNO is released from Hb and RBCs during deoxygenation, in proportion to the degree of Hb deoxygenation, to regulate vessels directly. In addition, we discuss how dysregulation of this system through genetic mutation in Hb or through disease is a common factor in oxygenation pathologies resulting from microcirculatory impairment, including sickle cell disease, ischemic heart disease, and heart failure. We then conclude by identifying potential therapeutic interventions to correct deficits in RBC-mediated vasodilation to improve oxygen delivery-steps toward effective microvasculature-targeted therapies. To the extent that diseases of the heart, lungs, and blood are associated with impaired tissue oxygenation, the development of new therapies based on the three-gas respiratory system have the potential to improve the well-being of millions of patients.

中文翻译：

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血红蛋白携带的一氧化氮在心血管生理中的作用：三气呼吸循环的发展。

持续供应氧气对于多细胞生物的生存至关重要。关于如何在微脉管系统中调节这种供应的理解已经从将红细胞（红细胞[RBC]）视为氧气的被动载体，发展到认识到Hb（血红蛋白）与氧气，二氧化碳和一氧化氮之间的复杂相互作用。三气呼吸循环-确保充足的氧气和营养物质输送，以满足当地的新陈代谢需求。在这种情况下，是血流而不是血氧含量是红细胞引起组织氧合的主要驱动力。本文中，我们回顾了导致对RBC功能有这种理解的实验路线。在佩鲁茨的立体化学模型中对血红蛋白中氧结合的变构调节的基础理解，盖顿观察到的血流自动调节（低氧血管舒张控制氧传递），以目前的理解为中心，血红蛋白的S-亚硝基化（即S-亚硝基血红蛋白； SNO-Hb）是依赖氧的血管舒张活性的提供者。值得注意的是，缺氧的血管舒张通过天然的S-亚硝基硫醇（SNO）补充的RBC和SNO-Hb本身来概括，由此SNO在脱氧过程中从Hb和RBC中释放出来，与Hb脱氧的程度成正比，从而直接调节血管。此外，我们讨论了通过Hb的基因突变或疾病导致的系统失调是微循环障碍（包括镰状细胞病，缺血性心脏病和心力衰竭）导致的氧合病理的常见因素。然后，我们通过确定潜在的治疗性干预措施来结束，以纠正RBC介导的血管舒张功能的不足，以改善向有效微血管靶向治疗的氧输送步骤。就心脏，肺部和血液疾病与组织氧合受损有关的程度而言，基于三气体呼吸系统的新疗法的开发具有改善数百万患者健康的潜力。