Regulation of the brain's vascular responses to oxygen

The mechanism of oxygen-induced cerebral vasoconstriction has been sought for more than a century. Using genetically altered mice to enhance or disrupt extracellular superoxide dismutase (EC-SOD, SOD3), we tested the hypothesis that this enzyme plays a critical role in the physiological response to oxygen in the brain by regulating nitric oxide (NO.) availability. Cerebral blood flow responses in these genetically altered mice to changes in Po-2 demonstrate that SOD3 regulates equilibrium between superoxide (.O-2(-)) and NO., thereby controlling vascular tone and reactivity in the brain. That SOD3 opposes inactivation of NO. is shown by absence of vasoconstriction in response to Po-2 in the hyperbaric range in SOD3(+/+) mice, whereas NO-dependent relaxation is attenuated in SOD3(-/-) mutants. Thus, EC-SOD promotes NO. vasodilation by scavenging .O-2(-) While hyperoxia opposes NO. and promotes constriction by enhancing endogenous O-.(2)- generation and decreasing basal vasodilator effects of NO..