title: VEGF can protect against blood brain barrier dysfunction, dendritic spine loss and spatial memory impairment in an experimental model of diabetes.
abstract: Clinical and experimental studies have shown a clear link between diabetes, vascular dysfunction and cognitive impairment. However, the molecular underpinnings of this association remain unclear. Since vascular endothelial growth factor (VEGF) signaling is important for maintaining vascular integrity and function, we hypothesized that vascular and cognitive impairment in the diabetic brain could be related to a deficiency in VEGF signaling. Here we show that chronic hyperglycemia (~8weeks) in a mouse model of type 1 diabetes leads to a selective reduction in the expression of VEGF and its cognate receptor (VEGF-R2) in the hippocampus. Correlating with this, diabetic mice showed selective deficits in spatial memory in the Morris water maze, increased vessel area, width and permeability in the dentate gyrus/CA1 region of the hippocampus and reduced spine densities in CA1 neurons. Chronic low dose infusion of VEGF in diabetic mice was sufficient to restore VEGF signaling, protect them from memory deficits, as well as vascular and synaptic abnormalities in the hippocampus. These findings suggest that a hippocampal specific reduction in VEGF signaling and resultant vascular/neuronal defects may underlie early manifestations of cognitive impairment commonly associated with diabetes. Furthermore, restoring VEGF signaling may be a useful strategy for preserving hippocampal-related brain circuitry in degenerative vascular diseases.
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Taylor
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada.
authors.forename: Dustin
authors.initials: D
authors.lastname: Trudeau
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada.
authors.forename: Brendan
authors.initials: B
authors.lastname: Arnold
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada.
authors.forename: Joshua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada.
authors.forename: Kim
authors.initials: K
authors.lastname: Gerrow
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada.
authors.forename: Kieran
authors.initials: K
authors.lastname: Summerfeldt
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Holmes
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada.
authors.forename: Akram
authors.initials: A
authors.lastname: Zamani
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada.
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Brocardo
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada; Department of Biology, University of Victoria, Victoria, BC V8P 5C2, Canada; Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. Electronic address: brownc@uvic.ca.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Brown
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000517:prevention & control / Q000523:psychology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D057967:Infusions, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065852:Spatial Memory / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Blood brain barrier; Dendritic spines; Diabetes; Hippocampus; Learning and memory; Vascular endothelial growth factor