EC-SOD is the only extracellular SOD isoform and the major SOD activity in blood vessels, which leads to increase NO bioavailability. Mice, RG7204 engineered to overexpress EC-SOD, have increased tolerance to both focal and global cerebral ischemia, while EC-SOD knock-outs exhibit enhanced damage. These data implicate an important role for EC-SOD ischemia/reperfusion pathologies, and suggest a therapeutic role for SOD mimetics. Previously, we showed that EC-SOD offers significant protection against oxidative stress-induced lung injury and brain injury induced by hyperoxia. In this study, we hypothesized that EC-SOD overexpression offers protection to the brain exposed to chronic hypoxia. This could be of importance to many diseases with compromised brain oxygenation. Adverse impacts of chronic or intermittent hypoxia on development, behavior, and academic achievement have been reported in many well-designed and controlled studies in children, as well as in a variety of studies in adults. Hypoxia, either chronic or intermittent, has been shown to increase oxidative stress and the generation of increased superoxide anion in the brain. In this study, we showed that overexpression of EC-SOD preserved the excitatory postsynaptic potential and hippocampal neural plasticity after exposure to hypoxia compared to wild type adult mice. We also have shown a clear correlation between overexpression of EC-SOD and decreased brain damage induced by chronic hypoxia exposure as indicated by functional, molecular, and structural studies. The protection against hypoxia-induced brain damage, offered by overexpression of EC-SOD, could be explained by different mechanisms. The oxidative stress produced by hypoxic insults leads to decreased SOD activity, increasing malondialdehyde, and lactic acid levels. Inactivation of EC-SOD activity has also been shown to be associated with 100-fold elevation in hypoxia-induced Epo gene expression, compared with wild-type controls. In our KI animal model, there was marked significant increase of SOD activity when compared to WT hypoxia. It is known that human EC-SOD exists as an active and inactive isoform. The marked significant increase of SOD activity in presence of little difference in the amount of EC-SOD among transgenic hypoxic animal vs. wild hypoxic animal, could be explained based on the possibility of having more active ECSOD in the hypoxic transgenic mice and less inactive EC-SOD and this accounts for the marked change in total SOD activity. When EC-SOD was overexpressed, a significant reduction in Epo gene induction has been shown in hypoxia both in vitro and in vivo. The inhibitory effect of EC-SOD on hypoxia-induced Epo expression could be due to partial stabilization of HIF-1alpha. It is known that hypoxia generated superoxide radicals are required for induction of HIF-1alpha activity and other downstream target genes. In KI animals with overexpression of EC-SOD, dismutation of free radicals will be increased compared to the WT group. This leads to decreased levels of ROS including superoxide, which plays a major role in stabilization and activation of HIF-1alpha. The resulted reduction of ROS concentration will decrease HIF-1alpha activation.