title: The heparan sulfate proteoglycan agrin contributes to barrier properties of mouse brain endothelial cells by stabilizing adherens junctions.
abstract: Barrier characteristics of brain endothelial cells forming the blood-brain barrier (BBB) are tightly regulated by cellular and acellular components of the neurovascular unit. During embryogenesis, the accumulation of the heparan sulfate proteoglycan agrin in the basement membranes ensheathing brain vessels correlates with BBB maturation. In contrast, loss of agrin deposition in the vasculature of brain tumors is accompanied by the loss of endothelial junctional proteins. We therefore wondered whether agrin had a direct effect on the barrier characteristics of brain endothelial cells. Agrin increased junctional localization of vascular endothelial (VE)-cadherin, β-catenin, and zonula occludens-1 (ZO-1) but not of claudin-5 and occludin in the brain endothelioma cell line bEnd5 without affecting the expression levels of these proteins. This was accompanied by an agrin-induced reduction of the paracellular permeability of bEnd5 monolayers. In vivo, the lack of agrin also led to reduced junctional localization of VE-cadherin in brain microvascular endothelial cells. Taken together, our data support the notion that agrin contributes to barrier characteristics of brain endothelium by stabilizing the adherens junction proteins VE-cadherin and β-catenin and the junctional protein ZO-1 to brain endothelial junctions.
authors.affiliation: Theodor Kocher Institute, University of Bern, Freiestrasse 1, 3012, Bern, Switzerland.
authors.forename: Esther
authors.initials: E
authors.lastname: Steiner
authors.forename: Gaby U
authors.initials: GU
authors.lastname: Enzmann
authors.forename: Ruth
authors.initials: R
authors.lastname: Lyck
authors.forename: Shuo
authors.initials: S
authors.lastname: Lin
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
authors.forename: Stephan
authors.initials: S
authors.lastname: Kröger
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism*; D018171:Agrin / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000166:cytology* / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D049109:Cell Proliferation; D002645:Chickens; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D057809:HEK293 Cells; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D051379:Mice; D055806:Microvessels / Q000166:cytology / Q000378:metabolism; D010539:Permeability; D055550:Protein Stability; D021381:Protein Transport; D013194:Staining and Labeling; D062826:Zonula Occludens-1 Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D018171:Agrin; D015703:Antigens, CD; D015820:Cadherins; D019812:Heparan Sulfate Proteoglycans; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin; D000099152:Cadherin 5
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