The mechanisms of cerebral vascular dysfunction and neuroinflammation by MMP-mediated degradation of VEGFR-2 in alcohol ingestion.
نویسندگان
چکیده
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. CONCLUSIONS 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.
منابع مشابه
Mechanisms of Cerebral Vascular dysfunction and Neuroinflammation by MMP-Mediated degradation of VeGFr-2 in alcohol ingestion
Received on: December 12, 2011; final version accepted on: February 22, 2012. From the Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE. the online-only data supplement is available with this article at http://atvb .ahajournals .org/lookup/suppl/doi:10 .1161/atVBaHa .112 .247668/-/ dC1 . Correspondence to James Haorah, Laboratory of Neur...
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عنوان ژورنال:
- Arteriosclerosis, thrombosis, and vascular biology
دوره 32 5 شماره
صفحات -
تاریخ انتشار 2012