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Ablation of MMP‐9 gene ameliorates paracellular permeability and fibrinogen‐amyloid beta plaque formation during hyperhomocysteinemia
Author(s) -
Muradashvili Nino,
Tyagi Reeta,
Tyagi Suresh C.,
Lominadze David
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.709.4
Subject(s) - paracellular transport , mmp9 , cystathionine beta synthase , chemistry , endocrinology , medicine , hyperhomocysteinemia , vascular permeability , blood–brain barrier , ve cadherin , mmp2 , inflammation , knockout mouse , matrix metalloproteinase , homocysteine , permeability (electromagnetism) , biology , biochemistry , gene , enzyme , endothelial stem cell , downregulation and upregulation , in vitro , central nervous system , cysteine , membrane
Many inflammatory and cognitive disorders including Alzheimer's disease are accompanied by hyperhomocysteinemia (HHcy). We tasted the hypothesis that HHcy increases microvascular permeability affecting mainly paracellular transport via activation of matrix metalloproteinase‐9 (MMP‐9) leading to an increased formation of fibrinogen (Fg) and β‐amyloid (Aβ) complex. Using a dual‐tracer probing method, changes in cerebrovascular permeability were assessed in male wild type (WT, C57BL/6J), cystathionine β‐synthase heterozygote (CBS+/−, a genetic model of HHcy), MMP‐9 gene knockout (MMP9−/−), and CBS and MMP‐9 double‐knockout (CBS+/−/MMP9−/−) mice. Expression of vascular endothelial cadherin (VE‐cadherin) and Fg‐Aβ plaque formation was assessed in mouse brain cryo‐sections. We found that cerebrovascular permeability in CBS+/− mice was mainly via paracellular transport pathway and it was greater than that in other groups. Expression of VE‐cadherin was lowest and Fg‐Aβ plaque formation was greatest in CBS+/− mice. Absence of MMP‐9 activity in MMP9−/− mice ameliorated these effects. Thus, HHcy increases cerebrovascular permeability by downregulating VE‐cadherin through MMP‐9 activation and enhances Fg‐Aβ plaque formation. These data may lead to identification of new targets for therapeutic intervention that can modulate inflammation‐induced cerebrovascular permeability.