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This Article Full Text Full Text (PDF) All Versions of this Article: 290/3/H1206    most recent 00376.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Lominadze, D. Articles by Tyagi, S. C. Search for Related Content PubMed PubMed Citation Articles by Lominadze, D. Articles by Tyagi, S. C.

Homocysteine causes cerebrovascular leakage in mice

Department of Physiology and Biophysics, Health Sciences Center, University of Louisville, Louisville, Kentucky

Submitted 17 April 2005 ; accepted in final form 25 October 2005

Elevated plasma homocysteine (Hcy) is associated with cerebrovascular disease and activates matrix metalloproteinases (MMPs), which lead to vascular remodeling that could disrupt the blood-brain barrier. To determine whether Hcy administration can increase brain microvascular leakage secondary to activation of MMPs, we examined pial venules by intravital video microscopy through a craniotomy in anesthetized mice. Bovine serum albumin labeled with fluorescein isothiocyanate (BSA-FITC) was injected into a carotid artery to measure extravenular leakage. Hcy (30 µM/total blood volume) was injected 10 min after FITC-BSA injection. Four groups of mice were examined: 1) wild type (WT) given vehicle; 2) WT given Hcy (WT + Hcy); 3) MMP-9 gene knockout given Hcy (MMP-9–/– + Hcy); and 4) MMP-9–/– with topical application of histamine (10^–4 M) (MMP-9–/– + histamine). In the WT + Hcy mice, leakage of FITC-BSA from pial venules was significantly (P < 0.05) greater than in the other groups. There was no significant leakage of pial microvessels in MMP-9–/– + Hcy mice. Increased cerebrovascular leakage in the MMP-9–/– + histamine group showed that microvascular permeability could still increase by a mechanism independent of MMP-9. Treatment of cultured mouse microvascular endothelial cells with 30 µM Hcy resulted in significantly greater F-actin formation than in control cells without Hcy. Treatment with a broad-range MMP inhibitor (GM-6001; 1 µM) ameliorated Hcy-induced F-actin formation. These data suggest that Hcy increases microvascular permeability, in part, through MMP-9 activation.

blood-brain barrier; F-actin; matrix metalloproteinases; matrix metalloproteinase-9; pial microvessels

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