Effects of Endothelial-Specific FoxO1 Deletion on Brain Microvasculature and Rescue of EAE-Induced Paralysis in Adult Mice
Faculty Mentor Information
Richard S. Beard
Presentation Date
7-2017
Abstract
The blood-brain barrier (BBB) is composed of an endothelial cell (EC) lining that serves as a barrier between circulating blood and surrounding brain tissues. BBB dysfunction can be attributed to weakened tight junctions between ECs, and contributes to many neurologic disorders, including multiple sclerosis and stroke. The transcription factor FoxO1 has been shown to downregulate EC barrier function during inflammation. Additionally, embryonic and neonatal FoxO1 knockout results in lethality and aberrant angiogenesis, respectively. Thus, the aims of this project were twofold: 1) Observe the effects of endothelial-specific FoxO1 deletion in adult mice, and 2) determine their resistance to a neuroinflammatory challenge. Deletion of FoxO1 was achieved by tamoxifen-induced, cre-mediated recombination in floxed FoxO1 mice, and morphometric analyses of brain microvasculature were performed with confocal fluorescence microscopy. In a second cohort, FoxO1-deficient mice were challenged with neuroinflammation via induction of experimental autoimmune encephalomyelitis (EAE). Our preliminary findings indicate that FoxO1-deficient mice are resistant to EAE-induced paralysis, whereas control mice experience tail paralysis and hind limb inhibition. These results suggest that although deletion of FoxO1 from ECs of mature brain microvessels does not alter their architecture or density, its deletion from the BBB appears to protect the microvessels from inflammation-mediated neuropathology.
Effects of Endothelial-Specific FoxO1 Deletion on Brain Microvasculature and Rescue of EAE-Induced Paralysis in Adult Mice
The blood-brain barrier (BBB) is composed of an endothelial cell (EC) lining that serves as a barrier between circulating blood and surrounding brain tissues. BBB dysfunction can be attributed to weakened tight junctions between ECs, and contributes to many neurologic disorders, including multiple sclerosis and stroke. The transcription factor FoxO1 has been shown to downregulate EC barrier function during inflammation. Additionally, embryonic and neonatal FoxO1 knockout results in lethality and aberrant angiogenesis, respectively. Thus, the aims of this project were twofold: 1) Observe the effects of endothelial-specific FoxO1 deletion in adult mice, and 2) determine their resistance to a neuroinflammatory challenge. Deletion of FoxO1 was achieved by tamoxifen-induced, cre-mediated recombination in floxed FoxO1 mice, and morphometric analyses of brain microvasculature were performed with confocal fluorescence microscopy. In a second cohort, FoxO1-deficient mice were challenged with neuroinflammation via induction of experimental autoimmune encephalomyelitis (EAE). Our preliminary findings indicate that FoxO1-deficient mice are resistant to EAE-induced paralysis, whereas control mice experience tail paralysis and hind limb inhibition. These results suggest that although deletion of FoxO1 from ECs of mature brain microvessels does not alter their architecture or density, its deletion from the BBB appears to protect the microvessels from inflammation-mediated neuropathology.