Endothelial-derived
nitric oxide (NO) is classically viewed as a regulator of vasomotor tone. NO plays an important role in regulating O(2) delivery through paracrine control of vasomotor tone locally and cardiovascular and respiratory responses centrally. Very soon after the cloning and functional characterization of the
endothelial nitric oxide synthase (eNOS), studies on the interaction between O(2) and NO made the paradoxical finding that
hypoxia led to decreases in eNOS expression and function. Why would decreases in O(2) content in tissues elicit a loss of a potent endothelial-derived
vasodilator? We now know that restricting our view of NO as a regulator of vasomotor tone or blood pressure limited deeper levels of mechanistic insight. Exciting new studies indicate that functional interactions between NO and O(2) exhibit profound complexity and are relevant to diseases states, especially those associated with
hypoxia in tissues. NOS
isoforms catalytically require O(2).
Hypoxia regulates steady-state expression of the
mRNA and
protein abundance of the NOS
enzymes. Animals genetically deficient in NOS
isoforms have perturbations in their ability to adapt to changes in O(2) supply or demand. Most interestingly, the intracellular pathways for O(2) sensing that evolved to ensure an appropriate balance of O(2) delivery and utilization intersect with NO signaling networks. Recent studies demonstrate that
hypoxia-inducible factor (HIF) stabilization and transcriptional activity is achieved through two parallel pathways: (1) a decrease in O(2)-dependent prolyl hydroxylation of HIF and (2) S-nitrosylation of HIF pathway components. Recent findings support a role for
S-nitrosothiols as
hypoxia-mimetics in certain
biological and/or disease settings, such as living at high altitude, exposure to small molecules that can bind NO, or
anemia.