Format

Send to

Choose Destination
  • This is a preview / test site. Please update your PubMed URL to pubmed.gov.
See comment in PubMed Commons below
Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1977-82. doi: 10.1073/pnas.0808698106. Epub 2009 Jan 27.

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

Author information

  • 1Corinne Goldsmith Dickinson Center for Multiple Sclerosis and Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

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.

PMID:
19174516
PMCID:
PMC2644149
DOI:
10.1073/pnas.0808698106
[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center