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Updated: Aug 15, 2026
Adult Mouse Venous Hypertension Model: Common Carotid Artery to External Jugular Vein Anastomosis.
Published on: January 27, 2015
Homocysteine causes cerebrovascular leakage in mice
David Lominadze1, Andrew M Roberts, Neetu Tyagi
1Department of Physiology and Biophysics, Health Sciences Center, A-1115, University of Louisville, Louisville, Kentucky 40292, USA. dglomi01@louisville.edu
Abstract:
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 microM/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 microM Hcy resulted in significantly greater F-actin formation than in control cells without Hcy. Treatment with a broad-range MMP inhibitor (GM-6001; 1 microM) ameliorated Hcy-induced F-actin formation. These data suggest that Hcy increases microvascular permeability, in part, through MMP-9 activation.
Insights
Elevated homocysteine (Hcy) increases brain microvascular leakage by activating matrix metalloproteinase-9 (MMP-9). This suggests MMP-9 plays a key role in Hcy-induced blood-brain barrier disruption.
Area of Science:
- Neuroscience
- Vascular Biology
- Biochemistry
Background:
- Elevated plasma homocysteine (Hcy) is linked to cerebrovascular diseases.
- Hcy activates matrix metalloproteinases (MMPs), potentially disrupting the blood-brain barrier (BBB).
Purpose of the Study:
- To investigate if Hcy administration increases brain microvascular leakage via MMP activation.
- To determine the role of MMP-9 in Hcy-induced BBB permeability.
Main Methods:
- Intravital video microscopy was used to examine pial venules in anesthetized mice.
- Fluorescein isothiocyanate-labeled bovine serum albumin (FITC-BSA) measured microvascular leakage.
- Experiments involved wild-type (WT) mice, MMP-9 gene knockout (MMP-9-/-) mice, Hcy administration, and MMP inhibitors.
Main Results:
- WT mice given Hcy showed significantly increased FITC-BSA leakage compared to controls.
- MMP-9-/- mice treated with Hcy exhibited no significant microvascular leakage.
- Hcy induced F-actin formation in endothelial cells, which was reduced by an MMP inhibitor.
Conclusions:
- Hcy administration increases brain microvascular permeability.
- MMP-9 activation is a significant mechanism contributing to Hcy-induced microvascular leakage.
- Targeting MMP-9 may offer therapeutic potential for Hcy-related cerebrovascular conditions.
