Abstract 124: Supplementation With Growth Differentiation Factor11 Promotes Tissue Recovery and Angiogenesis After Ischemic Stroke in Aged Mice

Abstract

Introduction: Growth differentiation factor (GDF) 11 levels decline with aging. This age-related loss of GDF11 has been implicated in a variety of age-related diseases. Supplementation with GDF11 reverses cardiac hypertrophy, bone loss, and pulmonary dysfunction in old mice, suggesting a rejuvenation effect of GDF11. Hypothesis: Brain levels of GDF11 would decline in aged animals, and that stroke would accelerate the age-related loss of GDF11. Exogenous administration of GDF11 would improve stroke outcomes in old mice. Methods: GDF11/8 levels were assessed in young and old mice and in postmortem human brain samples. In older mice, five days after MCAO, GDF11, and BrdU were administered for five days. Neurobehavioral assessments were performed during stroke recovery. MRI was used to determine cerebrospinal fluid (CSF), corpus callosum (CC) area, and percentage of brain tissue loss. Ten days post MCAo, brain expression of claudin5, collagen IV, BDNF, VEGF, pSmad2/3, activin type IIb receptor was assessed by western blotting. We performed immunohistochemistry to investigate IBA1, GFAP, NeuN, doublecortin, BDNF, MBP, synaptophysin, and CD31 immunoreactivity 30 days post-MCAo. Results: A decline in brain GDF11/8 was seen with age and after stroke in both mice and humans (p<0.05). Exogenous GDF11 supplementation reduced mortality and improved sensorimotor deficits thirty days after stroke. Treatment resulted in a reduction (p<0.05) in brain atrophy and CSF volume, and increased corpus callosum thickness as assessed by MRI. GDF11 treatment reduced gliosis, increased angiogenesis, and improved white matter integrity in aged mice. Conclusions: Brain GDF11/8 levels are reduced with aging, and after stroke. Exogenous GDF11 supplementation reduced mortality, decreased brain tissue damage, improved sensorimotor deficits, reduced gliosis, and increased angiogenesis in old mice after stroke.