Regulation of oxygen delivery to the body via hypoxic vasodilation

The respiratory system has traditionally been thought of as a two-gas model: hemoglobin (Hb) within red blood cells (RBC) binds oxygen in the lungs, delivers the oxygen to peripheral tissues, and binds carbon dioxide, which is returned to the lungs, released, and expired. However, fine-tuning of the system is required so that blood flow is preferentially shunted to tissues that have a greater need for oxygen. This mechanism, hypoxic vasodilation, is defined as the prompt vascular response to increased local demand for oxygen because of a change in metabolic activity in the absence of injury or disease (1, 2). This process involves detection of blood oxygen content by sensors and then a rapid transduction of the signal into a vasodilatory bioactivity (2). Emerging data suggest that Hb in the RBC not only functions as a vehicle to carry adequate amounts of oxygen to tissues, but also functions as an oxygen sensor and oxygen-responsive nitric oxide (NO) signal transducer, thereby regulating vascular tone (2, 3). In the past several decades, emerging findings suggest that the respiratory system is mediated by a third gas, NO, which regulates hypoxic vasodilation (2). This concept remains controversial, and three mechanisms have been proposed for RBC-dependent hypoxic vasodilation: adenosine triphosphate (ATP) release and subsequent activation of endothelial nitric oxide synthase (eNOS) (4⇓⇓–7); nitrite reduction to NO by deoxyhemoglobin (8, 9); and S-nitrosohemoglobin (SNO-Hb)-dependent bioactivity (1, 2, 10) (Fig. 1). In PNAS, Zhang et al. (11) present novel information adding a definitive genetic layer of proof supporting the third mechanism, the SNO-Hb pathway in RBC-dependent hypoxic vasodilation. Importantly, the phenotype of the mouse model used in this work illustrates the critical physiological importance this mechanism has in regulating tissue oxygenation. Three proposed mechanisms underlying hypoxic vasodilation. ATP …