VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown
| Autor: | Azeb Tadesse Argaw, Gareth R. John, Yueting Zhang, Blake T. Gurfein, Andleeb Zameer |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Central Nervous System
Vascular Endothelial Growth Factor A Cell Membrane Permeability Encephalomyelitis Autoimmune Experimental Endothelium Down-Regulation Biology Blood–brain barrier Occludin Mice medicine Animals Humans Barrier function Cells Cultured Cerebral Cortex Inflammation Multidisciplinary Tight junction Experimental autoimmune encephalomyelitis Lysosome-Associated Membrane Glycoproteins Membrane Proteins Biological Sciences medicine.disease Cell biology Endothelial stem cell Vascular endothelial growth factor A Disease Models Animal medicine.anatomical_structure Blood-Brain Barrier Immunology Cattle Endothelium Vascular |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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