The Key Role of Nitric Oxide in Hypoxia: Hypoxic Vasodilation and Energy Supply-Demand Matching

Significance: A mismatch between energy supply and demand induces tissue hypoxia with the potential to cause cell death and organ failure. Whenever arterial oxygen concentration is reduced, increases in blood flowhypoxic vasodilationoccur in an attempt to restore oxygen supply. Nitric oxide (NO) is a major signaling and effector molecule mediating the body's response to hypoxia, given its unique characteristics of vasodilation (improving blood flow and oxygen supply) and modulation of energetic metabolism (reducing oxygen consumption and promoting utilization of alternative pathways). Recent Advances: This review covers the role of oxygen in metabolism and responses to hypoxia, the hemodynamic and metabolic effects of NO, and mechanisms underlying the involvement of NO in hypoxic vasodilation. Recent insights into NO metabolism will be discussed, including the role for dietary intake of nitrate, endogenous nitrite (NO2-) reductases, and release of NO from storage pools. The processes through which NO levels are elevated during hypoxia are presented, namely, (i) increased synthesis from NO synthases, increased reduction of NO2- to NO by heme- or pterin-based enzymes and increased release from NO stores, and (ii) reduced deactivation by mitochondrial cytochrome c oxidase. Critical Issues: Several reviews covered modulation of energetic metabolism by NO, while here we highlight the crucial role NO plays in achieving cardiocirculatory homeostasis during acute hypoxia through both vasodilation and metabolic suppression. Future Directions: We identify a key position for NO in the body's adaptation to an acute energy supply-demand mismatch. Antioxid. Redox Signal. 19, 1690-1710.