title: Delayed inhibition of VEGF signaling after stroke attenuates blood-brain barrier breakdown and improves functional recovery in a comorbidity-dependent manner.
abstract: Diabetes is a common comorbidity in stroke patients and a strong predictor of poor functional outcome. To provide a more mechanistic understanding of this clinically relevant problem, we focused on how diabetes affects blood-brain barrier (BBB) function after stroke. Because the BBB can be compromised for days after stroke and thus further exacerbate ischemic injury, manipulating its function presents a unique opportunity for enhancing stroke recovery long after the window for thrombolytics has passed. Using a mouse model of Type 1 diabetes, we discovered that ischemic stroke leads to an abnormal and persistent increase in vascular endothelial growth factor receptor 2 (VEGF-R2) expression in peri-infarct vascular networks. Correlating with this, BBB permeability was markedly increased in diabetic mice, which could not be prevented with insulin treatment after stroke. Imaging of capillary ultrastructure revealed that BBB permeability was associated with an increase in endothelial transcytosis rather than a loss of tight junctions. Pharmacological inhibition (initiated 2.5 d after stroke) or vascular-specific knockdown of VEGF-R2 after stroke attenuated BBB permeability, loss of synaptic structure in peri-infarct regions, and improved recovery of forepaw function. However, the beneficial effects of VEGF-R2 inhibition on stroke recovery were restricted to diabetic mice and appeared to worsen BBB permeability in nondiabetic mice. Collectively, these results suggest that aberrant VEGF signaling and BBB dysfunction after stroke plays a crucial role in limiting functional recovery in an experimental model of diabetes. Furthermore, our data highlight the need to develop more personalized stroke treatments for a heterogeneous clinical population.
authors.affiliation: Division of Medical Sciences and.
authors.forename: Patrick
authors.initials: P
authors.lastname: Reeson
authors.affiliation: Division of Medical Sciences and.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Tennant
authors.affiliation: Division of Medical Sciences and.
authors.forename: Kim
authors.initials: K
authors.lastname: Gerrow
authors.affiliation: Division of Medical Sciences and.
authors.forename: Josh
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Medical Sciences and.
authors.forename: Sammy
authors.initials: S
authors.lastname: Weiser Novak
authors.affiliation: Division of Medical Sciences and.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Thompson
authors.affiliation: Division of Medical Sciences and.
authors.forename: Krista-Linn
authors.initials: KL
authors.lastname: Lockhart
authors.affiliation: Division of Medical Sciences and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Holmes
authors.affiliation: Division of Medical Sciences and Department of Biology, University of Victoria, Victoria, British Columbia V8P 5C2, Canada, Department of Cellular and Physiological Sciences and.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Nahirney
authors.affiliation: Division of Medical Sciences and Department of Biology, University of Victoria, Victoria, British Columbia V8P 5C2, Canada, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada brownc@uvic.ca.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Brown
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D002196:Capillaries / Q000473:pathology / Q000648:ultrastructure; D049229:Dendritic Spines / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000648:ultrastructure; D015870:Gene Expression; D007211:Indoles / Q000494:pharmacology; D007238:Infarction / Q000150:complications / Q000473:pathology; D007328:Insulin / Q000627:therapeutic use; D051379:Mice; D010539:Permeability / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D020521:Stroke / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013569:Synapses / Q000473:pathology; D057900:Transcytosis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism*
chemical_list: D007211:Indoles; D007328:Insulin; D011758:Pyrroles; C116890:Semaxinib; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: blood–brain barrier; dendritic spines; diabetes; imaging; stroke; vascular endothelial growth factor
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