Stress Induced Angioplasticity Is Protective In Experimental Autoimmune Encephalomyelitis (EAE) (P1.180)

OBJECTIVE: Identify new molecular targets that promote repair in neurodegenerative disease. BACKGROUND: In the brain, tissue survival is dependent on maintenance of metabolic homeostasis. In response to stress cells of the blood brain barrier make fine tuned regulatory adaptations that result in a continuous matching of tissue oxygen with capillary density (adaptive angioplasticity) that promotes survival. Loss of adaptive angioplasticity may underlie the pathophysiology of a number of neurodegenerative diseases including multiple sclerosis (MS). We hypothesize that treatment strategies that restore vascular homeostasis will improve tissue repair, ameliorate inflammatory activity, mitigate secondary injury and improve clinical outcome in myelin oligodendrocyte glycoprotein (MOG) peptide-induced experimental autoimmune encephalomyelitis (EAE). DESIGN/METHODS: C57BL/6 mice were immunized with MOG35-55. Following development of clinical symptoms mice were stratified for disease severity then placed in normobaric hypoxia chambers calibrated to 10% oxygen for up to 3 weeks. Clinical scores and weight were evaluated daily and spinal cord harvested. Lumbar spinal cord sections were stained using Hematoxylin-Eosin (H+E) to visualize leukocyte infiltration and for the glucose transporter protein (Glut-1) to determine vascular density. Mice were also exposed to hypoxia for 3 weeks then removed to normal oxygen to determine relapse rate. RESULTS: Exposure to chronic mild hypoxia induced angioplasticity in immunized and sham immunized control mice. Mild hypoxia ameliorated the signs and symptoms of chronic EAE during the treatment period. When animals were returned to normoxic environments for 21 days only one mouse relapsed. Induction of angioplasticity was associated with induction of HIF-1α, increased vascular density and decreased evidence of leukocyte migration to the spinal cord. Induction of angioplasticity decreased endothelial activation in the spinal cords and augmented the production of stress proteins. CONCLUSIONS: Stress induced adaptive angioplasticity promotes recovery of EAE. Mechanistic insight may lead to the identification of novel therapeutic targets that will promote tissue repair. Disclosure: Dr. Katyshev has nothing to disclose. Dr. Esen has nothing to disclose. Dr. Katysheva has nothing to disclose. Dr. Serkin has nothing to disclose. Dr. Dore-Duffy has nothing to disclose.