title: Mice deficient in endothelial α5 integrin are profoundly resistant to experimental ischemic stroke.
abstract: Stroke is a disease in dire need of better therapies. We have previously shown that a fragment of the extracellular matrix proteoglycan, perlecan, has beneficial effects following cerebral ischemia via the α5β1 integrin receptor. We now report that endothelial cell selective α5 integrin deficient mice (α5 KO) are profoundly resistant to ischemic infarct after transient middle cerebral artery occlusion. Specifically, α5 KOs had little to no infarct 2-3 days post-stroke, whereas controls had an increase in mean infarct volume over the same time period as expected. Functional outcome is also improved in the α5 KOs compared with controls. Importantly, no differences in cerebrovascular anatomy or collateral blood flow were noted that could account for this difference in ischemic injury. Rather, we demonstrate that α5 KOs have increased blood-brain barrier integrity (increased expression of claudin-5, and absent brain parenchymal IgG extravasation) after stroke compared with controls, which could explain their resistance to ischemic injury. Additionally, inhibition of α5 integrin in vitro leads to decreased permeability of brain endothelial cells following oxygen-glucose deprivation. Together, these findings indicate endothelial cell α5 integrin plays an important role in stroke outcome and blood-brain barrier integrity, suggesting that α5 integrin could be a novel therapeutic target for stroke.
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.|Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Roberts
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors.forename: Leon
authors.initials: L
authors.lastname: de Hoog
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA gregorybix@uky.edu.|Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY, USA.|Department of Neurology, University of Kentucky, Lexington, KY, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Bix
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D020520:Brain Infarction / Q000473:pathology; D002545:Brain Ischemia / Q000473:pathology*; D062507:Claudin-5 / Q000096:biosynthesis; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000139:chemically induced*; D042783:Endothelial Cells / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D039482:Integrin alpha5 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D020521:Stroke / Q000209:etiology* / Q000473:pathology
chemical_list: D062507:Claudin-5; D039482:Integrin alpha5
keywords: blood-brain barrier; extracellular matrix; middle cerebral artery occlusion; transgenic; α5β1