期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 290, 期 3, 页码 H1206-H1213出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00376.2005
关键词
blood-brain barrier; F-actin; matrix metalloproteinases; matrix metalloproteinase-9; pial microvessels
资金
- NHLBI NIH HHS [HL-71010, HL-74185, R01 HL071010, R01 HL080394, R01 HL080394-01A2, R01 HL074185] Funding Source: Medline
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 mu M/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 mu M Hcy resulted in significantly greater F-actin formation than in control cells without Hcy. Treatment with a broad-range MMP inhibitor (GM-6001; 1 mu M) ameliorated Hcy-induced F-actin formation. These data suggest that Hcy increases microvascular permeability, in part, through MMP-9 activation.
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