Regulation of the Brain’s Vascular Responses to Oxygen

Abstract

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 Po₂ demonstrate that SOD3 regulates equilibrium between superoxide (·O₂⁻) 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 Po₂ in the hyperbaric range in SOD3^+/+ mice, whereas NO-dependent relaxation is attenuated in SOD3^−/− mutants. Thus, EC-SOD promotes NO^·vasodilation by scavenging ·O₂⁻ while hyperoxia opposes NO^·and promotes constriction by enhancing endogenous ·O₂⁻ generation and decreasing basal vasodilator effects of NO^·.