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1 Physiology and Biophysics, University of Louisville, Louisville, KY, USA
* To whom correspondence should be addressed. E-mail: dglomi01{at}louisville.edu.
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 if 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 ten minutes 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 knock-out given Hcy (MMP-9 -/- + Hcy); and MMP-9-/- with topical application of histamine(10-4 M) (MMP-9-/- + histamine). In WT + Hcy, 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 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.
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