While the pathologic events associated with multiple sclerosis (MS), diffuse axonal injury, cognitive damage, and white matter plaques, have been known for some time, the etiology of MS is still unknown and therapeutic efforts are somewhat disappointing. This may be due to a lack of fundamental knowledge on how to buffer the brain from secondary injury following immune attack. Maintenance of central nervous system (CNS) homeostasis is a complex set of regulatory adjustments by the neurovascular unit that includes induction of adaptive angiogenesis. Although aspects of adaptive angiogenesis are induced in MS and experimental autoimmune encephalomyelitis (EAE), vascular remodeling is ineffective and the balance between metabolic need and oxygen (O(2)) and glucose availability is disrupted.We hypothesized that restoration of metabolic homeostasis in the CNS would ameliorate tissue damage and promote repair in myelin oligodendrocyte glycoprotein(MOG)-induced EAE in mice. Exposure of animals to chronic mild hypoxia (10% O(2)) increased vascular density and significantly delayed onset and severity of clinical EAE. When animals were exposed to hypoxia after the onset of clinical symptoms, the severity of chronic inflammatory disease was reduced or even inhibited. In addition, spinal cord pathology was decreased.While the mechanism of protection is unclear, results suggest that hypoxia has therapeutic potential in EAE.