The mechanisms of cerebral vascular dysfunction and neuroinflammation by MMP-mediated degradation of VEGFR-2 in alcohol ingestion

P. M.Abdul Muneer, Saleena Alikunju, Adam M. Szlachetka, James Haorah

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Objective-: Blood-brain barrier (BBB) dysfunction caused by activation of matrix metalloproteinases (MMPs) is a pathological feature in vascular/neurological disease. We describe the mechanisms of BBB dysfunction and neuroinflammation as a result of MMP-3/9 activation and disruption of vascular endothelial growth factor (VEGF)-A/VEGFR-2 interaction, impairing effective angiogenesis. Methods And Results-: We investigate the hypothesis in human brain endothelial cells and animal model of chronic alcohol ingestion. Proteome array analysis, zymography, immunofluorescence, and Western blotting techniques detected the activation, expression, and levels of MMP-3 and MMP-9. We found that degradation of VEGFR-2 and BBB proteins, for example, occludin, claudin-5, and ZO-1 by MMP-3/9, causes rupture of capillary endothelium and BBB leakiness. Impairment of BBB integrity was demonstrated by increased permeability of dye tracers and Fluo-3/calcein-AM-labeled monocyte adhesion or infiltration and decrease in transendothelial electric resistance. Alcohol-induced degradation of endothelial VEGFR-2 by MMP-3/9 led to a subsequent elevation of cellular/serum VEGF-A level. The decrease in VEGFR-2 with subsequent increase in VEGF-A level led to apoptosis and neuroinflammation via the activation of caspase-1 and IL-1β release. The use of MMPs, VEGFR-2, and caspase-1 inhibitors helped to dissect the underlying mechanisms. Conclusion-: Alcohol-induced MMPs activation is a key mechanism for dysfunction of BBB via degradation of VEGFR-2 protein and activation of caspase-1 or IL-1β release. Targeting VEGF-induced MMP-3/9 activation can be a novel preventive approach to vascular inflammatory disease in alcohol abuse.

Original languageEnglish (US)
Pages (from-to)1167-1177
Number of pages11
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume32
Issue number5
DOIs
StatePublished - May 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Keywords

  • Alcohol
  • Blood-brain barrier
  • Matrix metalloproteinase
  • Vascular endothelial growth factor
  • Vascular endothelial growth factor-R2
  • Vascular inflammation

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