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MMP-9 expression is associated with leukocytic but not endothelial markers in brain arteriovenous malformations
Yongmei Chen1, Yongfeng Fan, K Y Trudy Poon
1Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94110, USA.
Abstract:
Brain arteriovenous malformations (BAVM) have high matrix metalloproteinase-9 (MMP-9) expression, the source of which is unclear. We hypothesized MMP-9 production might be due to inflammation in BAVM. Compared to control brain tissues (n = 5), BAVM tissue (n = 139) had a higher expression (by ELISA) of myeloperoxidase (MPO) (193 +/- 189 vs. 6 +/- 3, ng/mg, P < .001), MMP-9 (28 +/- 32 vs. 0.7 +/- 0.6, ng/mg, P < .001), and IL-6 (102 +/- 218 vs. 0.1 +/- 0.1, pg/mg, P < .001), but not eNOS (114 +/- 87 vs. 65 +/- 9, pg/mg, P = .09). MMP-9 expression in BAVM highly correlated with myeloperoxidase (R2 = .76, P < .001), as well as with IL-6 (R2 = .32, P < .001). In contrast, MMP-9 in BAVM poorly correlated with the endothelial marker, eNOS (R2 = .03, P = .05), and CD31 (R2 = .004, P = .57). Compared to non-embolized patients (n = 46), patients with pre-operative embolization (n = 93) had higher levels of myeloperoxidase (236 +/- 205 vs. 106 +/- 108, ng/mg, P < .001) and MMP-9 (33 +/- 35 vs. 16 +/- 20, ng/mg, P < .001), however the correlation between MMP-9 and myeloperoxidase was equally strong for both groups (R2 = .69, n = 93, P < .001, for both). MMP-9 expression correlated with the lipocalin-MMP-9 complex, suggesting neutrophils as the MMP-9 source. MPO co-localized with majority of MMP-9 signal by immunohistochemistry. Our data suggest that inflammation is a prominent feature of BAVM lesional phenotype, and neutrophils appear to be a major source of MMP-9 in these lesions.
Insights
Inflammation drives matrix metalloproteinase-9 (MMP-9) production in brain arteriovenous malformations (BAVM). Neutrophils are identified as a primary source of MMP-9 in these vascular lesions.
Area of Science:
- Neuroscience
- Vascular Biology
- Immunology
Background:
- Brain arteriovenous malformations (BAVM) exhibit elevated matrix metalloproteinase-9 (MMP-9) expression.
- The cellular source of MMP-9 in BAVM remains undetermined.
- Inflammation is a potential contributor to MMP-9 production in BAVM.
Purpose of the Study:
- To investigate the source of high MMP-9 expression in BAVM.
- To determine if inflammation contributes to MMP-9 production in BAVM.
- To explore the role of neutrophils in MMP-9 expression within BAVM.
Main Methods:
- Enzyme-linked immunosorbent assay (ELISA) was used to quantify MMP-9, myeloperoxidase (MPO), IL-6, and eNOS in BAVM and control tissues.
- Correlation analyses were performed to assess relationships between MMP-9, MPO, IL-6, and eNOS.
- Immunohistochemistry was employed to examine the co-localization of MPO and MMP-9.
- MMP-9 expression was compared between non-embolized and embolized BAVM patients.
Main Results:
- BAVM tissues showed significantly higher expression of MPO, MMP-9, and IL-6 compared to controls.
- MMP-9 expression strongly correlated with MPO and IL-6 levels in BAVM.
- MMP-9 expression showed a weak correlation with endothelial markers eNOS and CD31.
- Pre-operative embolization was associated with increased MPO and MMP-9 levels.
- Immunohistochemistry revealed co-localization of MPO and MMP-9, suggesting neutrophils as the source.
Conclusions:
- Inflammation is a significant feature of the BAVM lesional phenotype.
- Neutrophils are a major source of MMP-9 in brain arteriovenous malformations.
- These findings highlight the inflammatory component in BAVM pathogenesis and suggest potential therapeutic targets.
