title: VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown.
abstract: Breakdown of the blood-brain barrier (BBB) is an early and significant event in CNS inflammation. Astrocyte-derived VEGF-A has been implicated in this response, but the underlying mechanisms remain unresolved. Here, we identify the endothelial transmembrane tight junction proteins claudin-5 (CLN-5) and occludin (OCLN) as targets of VEGF-A action. Down-regulation of CLN-5 and OCLN accompanied up-regulation of VEGF-A and correlated with BBB breakdown in experimental autoimmune encephalomyelitis, an animal model of CNS inflammatory disease. In cultures of brain microvascular endothelial cells, VEGF-A specifically down-regulated CLN-5 and OCLN protein and mRNA. In mouse cerebral cortex, microinjection of VEGF-A disrupted CLN-5 and OCLN and induced loss of barrier function. Importantly, functional studies revealed that expression of recombinant CLN-5 protected brain microvascular endothelial cell cultures from a VEGF-induced increase in paracellular permeability, whereas recombinant OCLN expressed under the same promoter was not protective. Previous studies have shown CLN-5 to be a key determinant of trans-endothelial resistance at the BBB. Our findings suggest that its down-regulation by VEGF-A constitutes a significant mechanism in BBB breakdown.
authors.affiliation: Corinne Goldsmith Dickinson Center for Multiple Sclerosis and Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Azeb Tadesse
authors.initials: AT
authors.lastname: Argaw
authors.forename: Blake T
authors.initials: BT
authors.lastname: Gurfein
authors.forename: Yueting
authors.initials: Y
authors.lastname: Zhang
authors.forename: Andleeb
authors.initials: A
authors.lastname: Zameer
authors.forename: Gareth R
authors.initials: GR
authors.lastname: John
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D002417:Cattle; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology; D002540:Cerebral Cortex; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology*; D006801:Humans; D007249:Inflammation; D051907:Lysosomal Membrane Proteins; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D062793:Occludin; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: C113332:CLN5 protein, human; D051907:Lysosomal Membrane Proteins; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A