Abstract
Systemic hypoxia is characterized by peripheral vasodilation and pulmonary vasoconstriction. However, the system-wide mechanism for signaling hypoxia remains unknown. Accumulating evidence suggests that hemoglobin (Hb) in RBCs may serve as an O2 sensor and O2-responsive NO signal transducer to regulate systemic and pulmonary vascular tone, but this remains unexamined at the integrated system level. One residue invariant in mammalian Hbs, β-globin cysteine93 (βCys93), carries NO as vasorelaxant S-nitrosothiol (SNO) to autoregulate blood flow during O2 delivery. βCys93Ala mutant mice thus exhibit systemic hypoxia despite transporting O2 normally. Here, we show that βCys93Ala mutant mice had reduced S-nitrosohemoglobin (SNO-Hb) at baseline and upon targeted SNO repletion and that hypoxic vasodilation by RBCs was impaired in vitro and in vivo, recapitulating hypoxic pathophysiology. Notably, βCys93Ala mutant mice showed marked impairment of hypoxic peripheral vasodilation and developed signs of pulmonary hypertension with age. Mutant mice also died prematurely with cor pulmonale (pulmonary hypertension with right ventricular dysfunction) when living under low O2. Altogether, we identify a major role for RBC SNO in clinically relevant vasodilatory responses attributed previously to endothelial NO. We conclude that SNO-Hb transduces the integrated, system-wide response to hypoxia in the mammalian respiratory cycle, expanding a core physiological principle.
Highlights
The physiological response to systemic hypoxia is a foundational aspect of the respiratory cycle through which O2 is delivered to tissues
We have previously shown that native β-globin Cys93 (βCys93) mutant red blood cell (RBC) induce vasodilation less effectively under hypoxia than control RBCs [7] and that human RBCs loaded physiologically with nitric oxide (NO) gas recapitulate hypoxic vasodilation by native RBCs [15]
In working with mouse RBCs, we noted that Hb is not modified by exogenous CysNO as readily as is Hb within human RBCs, and that metHb formed in very high amounts
Summary
The physiological response to systemic hypoxia is a foundational aspect of the respiratory cycle through which O2 is delivered to tissues. Accumulating evidence suggests that the respiratory cycle is a 3-gas system in which hemoglobin (Hb) is a carrier for not just two, but three gasses in blood: O2, CO2, and nitric oxide (NO) [2, 3], and that Hb acts as an O2-responsive NO-based vasodilator that matches tissue perfusion to oxygen demand [4, 5]. This effect, termed auto-regulation of blood flow [5], acts locally within individual capillaries and microvascular beds to increase red blood cell (RBC) transit, and functions in direct proportion to Hb desaturation to ensure metabolic coupling (together with vasodilators released from hypoxic tissues for purposes of capillary recruitment [6]). Mice mutated to be unable to dispense NO from Hb are profoundly hypoxic despite RBCs carrying normal amounts of O2 [7]
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