VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown

AT Argaw, BT Gurfein, Y Zhang… - Proceedings of the …, 2009 - National Acad Sciences
AT Argaw, BT Gurfein, Y Zhang, A Zameer, GR John
Proceedings of the National Academy of Sciences, 2009National Acad Sciences
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 …
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.
National Acad Sciences