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Plasma Matrix Metalloproeteinase-9 Is Associated with Seizure and Angioarchitecture Changes in Brain Arteriovenous Malformations

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Abstract

Both angiogenesis and inflammation contribute to activation of matrix metalloproeteinase-9 (MMP-9), which dissolves the extracellular matrix, disrupts the blood–brain barrier, and plays an important role in the pathogenesis of brain arteriovenous malformations (BAVMs). The key common cytokine in both angiogenesis and inflammation is interleukin 6 (IL-6). Previous studies have shown elevated systemic MMP-9 and decreased systemic vascular endothelial growth factor (VEGF) in BAVM patients. However, the clinical utility of plasma cytokines is unclear. The purpose of this study is to explore the relationship between plasma cytokines and the clinical presentations of BAVMs. Prospectively, we recruited naive BAVM patients without hemorrhage as the experimental group and unruptured intracranial aneurysm (UIA) patients as the control group. All patients received digital subtraction angiography, and plasma cytokines were collected from the lesional common carotid artery. Plasma cytokine levels were determined using a commercially available, monoclonal antibody–based enzyme-linked immunosorbent assay. Subgroup analysis based on hemorrhagic presentation and angiograchitecture was done for the BAVM group. Pearson correlations were calculated for the covariates. Means and differences for continuous and categorical variables were compared using Student’s t and χ2 tests respectively. Plasma MMP-9 levels were significantly higher in the BAVM group (42,945 ± 29,991 pg/mL) than in the UIA group (28,270 ± 17,119 pg/mL) (p < 0.001). Plasma MMP-9 levels in epileptic BAVMs (57,065 ± 35,732; n = 9) were higher than in non-epileptic BAVMs (35,032 ± 28,301; n = 19) (p = 0.049). Lower plasma MMP-9 levels were found in cases of BAVM with angiogenesis and with peudophlebitis. Plasma MMP-9 is a good biomarker reflecting ongoing vascular remodeling in BAVMs. Angiogenesis and pseudophlebitis are two angioarchitectural signs that reflect MMP-9 activities and can potentially serve as imaging biomarkers for epileptic BAVMs.

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 Data availability

All patient characteristics and data are available upon requests to the correspondent author.

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Abbreviations

BAVM:

Brain arteriovenous malformation

IL-1b:

Interlukin 1b

IL-6:

Interleukin-6

MMP-9:

Matrix metalloproteinase-9

TGFα:

Tumor growth factor α

VEGF:

Vascular endothelial growth factor

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Acknowledgements

We would like to thank Joseph Lavallee for English editing and Miss Hsin-Yi Huang for statistical assistance.

Funding

This work was supported by the Taipei Veterans General Hospital (grant number: V110-C- 056, V110C-080), Taiwan’s Ministry of Science and Technology (grant number: MOST-106–2314-B-010 -015 –MY2, MOST 108–2321-B-010–012-MY2, MOST 109–2314-B-075–055), and the Brain Research Center, National Yang Ming Chiao Tung University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (grant number: MOE 109BRC-B408) in Taiwan.

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Authors and Affiliations

  1. Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan

    Yo-Tsen Liu

  2. Brain Research Centre, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan

    Yo-Tsen Liu

  3. School of Medicine, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan

    Yo-Tsen Liu, Cheng-Chia Lee, Chun-Fu Lin, Hsiu-Mei Wu, Wan-Yuo Guo, Huai-Che Yang, Feng-Chi Chang, Kang-Du Liou & Chung-Jung Lin

  4. Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Yo-Tsen Liu

  5. Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan

    Cheng-Chia Lee, Chun-Fu Lin, Huai-Che Yang & Kang-Du Liou

  6. Department of Radiology, Taipei Veterans General Hospital, No. 201, Shipai Rd., Sec. 2, Beitou District, Taipei, 112, Taiwan

    Hsiu-Mei Wu, Wan-Yuo Guo, Feng-Chi Chang & Chung-Jung Lin

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Contributions

Concept of study design: C.-J. Lin, Y.-T. Liu, H.-M. Wu, and H.-C. Yang. Data collection and statistics: C.-J. Lin, Y.-T. Liu, F.-C. Chang, H.-C. Yang, and K.-D. Liou. Manuscript draft: C.-J. Lin, Y.-S. Hu, C.-C. Lee, and Y.-T. Liu. Integration of the manuscript: C.-J. Lin, W.-Y. Guo, H.-M. Wu, K.-D. Liou, and Y.-T. Liu.

Corresponding author

Correspondence to Chung-Jung Lin.

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All the participants have given their signed informed consent. This study was approved by the local ethnic committee (IRB number: 2020–06-005C).

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The authors declare no competing interests. MMP-9 regardless hemorrhage or not.

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Yo-Tsen Liu and Cheng-Chia Lee contribute equally as first authors.

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Liu, YT., Lee, CC., Lin, CF. et al. Plasma Matrix Metalloproeteinase-9 Is Associated with Seizure and Angioarchitecture Changes in Brain Arteriovenous Malformations. Mol Neurobiol 59, 5925–5934 (2022). https://doi.org/10.1007/s12035-022-02958-5

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