Early Inhibition of MMP Activity in Ischemic Rat Brain Promotes Expression of Tight Junction Proteins and Angiogenesis During Recovery
Open accessAbstract
In cerebral ischemia, matrix metalloproteinases (MMPs) have a dual role by acutely disrupting tight junction proteins (TJPs) in the blood-brain barrier (BBB) and chronically promoting angiogenesis. Since TJP remodeling of the neurovascular unit (NVU) is important in recovery and early inhibition of MMPs is neuroprotective, we hypothesized that short-term MMP inhibition would reduce infarct size and promote angiogenesis after ischemia. Adult spontaneously hypertensive rats had a transient middle cerebral artery occlusion with reperfusion. At the onset of ischemia, they received a single dose of the MMP inhibitor, GM6001. They were studied at multiple times up to 4 weeks with immunohistochemistry, biochemistry, and magnetic resonance imaging (MRI). We observed newly formed vessels in peri-infarct regions at 3 weeks after reperfusion. Dynamic contrast-enhanced MRI showed BBB opening in new vessels. Along with the new vessels, pericytes expressed zonula occludens-1 (ZO-1) and MMP-3, astrocytes expressed ZO-1, occludin, and MMP-2, while endothelial cells expressed claudin-5. The GM6001, which reduced tissue loss at 3 to 4 weeks, significantly increased new vessel formation with expression of TJPs and MMPs. Our results show that pericytes and astrocytes act spatiotemporally, contributing to extraendothelial TJP formation, and that MMPs are involved in BBB restoration during recovery. Early MMP inhibition benefits neurovascular remodeling after stroke.
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The breakdown of claudin-5 can be attributed to VEGF-mediated MMP expression.
“several studies in ischaemic stroke, a neurological disease characterized by BBB impairment, suggest that the breakdown of claudin-5 can be attributed to VEGF-mediated matrix metalloproteinase (MMP) expression [52–55].”
From Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain (2022) · cites this paper as [52]
The Introduction (page not provided) says MMP-2 and MMP-9 degrade claudin-5 after ischemic reperfusion. The Discussion (page not provided) reports VEGF and MMP expression in cells near the infarct, but does not say VEGF induces MMP expression or that VEGF mediates the claudin-5 breakdown. (LLM, conf=0.86)
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- Authors
- Yang, Y., Thompson, J. F., Taheri, S., Salayandia, V. M., McAvoy, T. A., Hill, J. W., Yang, Y., Estrada, E. Y., & Rosenberg, G. A.
- Affiliations
- University of New Mexico Health Sciences Center (US)
- Medical University of South Carolina (US)
- Corresponding author
- Yang, Yirong
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2013-04-10
- Volume
- 33
- Issue
- 7
- Pages
- 1104-1114
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC3705440
- OpenAlex
- W2051617804
- Cited by
- 147
- References
- 40
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 10 · 2023: 11 · 2022: 10 · 2021: 9 · 2020: 9 · 2019: 10 · 2018: 14 · 2017: 12 · 2016: 15 · 2015: 14 · 2014: 17 · 2013: 2
- FWCI
- 8.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS045847)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- matrix metalloproteinases, matrix metalloproteinase inhibition, GM6001, cerebral ischemia, stroke, tight junction proteins, blood-brain barrier, angiogenesis, pericytes, astrocytes, zonula occludens-1, claudin-5, occludin, infarct size, reperfusion, spontaneously hypertensive rats, middle cerebral artery occlusion
- MeSH terms
- Animals, Blood-Brain Barrier, Brain Ischemia, Dipeptides, Magnetic Resonance Imaging, Male, Rats, Inbred SHR, Blotting, Western, Cell Death, Neovascularization, Physiologic, In Situ Nick-End Labeling, Matrix Metalloproteinases, Rats, DNA Fragmentation, Matrix Metalloproteinase Inhibitors, Tight Junction Proteins
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