Early VEGF inhibition attenuates blood-brain barrier disruption in ischemic rat brains by regulating the expression of MMPs
Open accessAbstract
Vascular endothelial growth factor (VEGF) inhibition has been demonstrated to be an effective strategy in preserving the integrity of the blood-brain barrier (BBB) in patients with acute ischemic stroke. Loss of the BBB is the key event associated with morbidity and mortality in these patients. However, the underlying mechanisms remain poorly understood. In the present study, the effects of VEGF inhibition and the possible mechanism that underlies acute cerebral ischemia in rats was investigated. Following the induction of transient middle cerebral artery occlusion for a 90‑min period, either an anti‑VEGF neutralizing antibody (RB‑222; 5 or 10 µg), or IgG (control), was administered by intracerebroventricular injection at 1 h following reperfusion. Functional outcomes, BBB leakage, brain edema, microvessel numbers and the relative protein levels of VEGF, matrix metalloproteinase (MMP)-2, MMP-9, occludin and collagen-IV were then determined using neurological assessments, Evans Blue staining, brain water content, CD31 staining and western blotting. Treatment with RB‑222 at a dose of 5 and 10 µg significantly improved neurological functional outcomes and diminished infarct size, BBB leakage and brain edema compared with the MCAO and IgG groups at 24 h following reperfusion; 10 µg RB‑222 was more effective than a 5 µg dose of the antibody. In addition, RB‑222 reduced the number of immature microvessels, which subsequently attenuated BBB permeability. RB‑222 significantly repressed VEGF expression as well as decreased MMP‑2 and MMP‑9 expression. However, it enhanced occludin and collagen‑IV levels in the ischemic rat brain compared with the MCAO and IgG groups. Taken together, the results indicate that early inhibition of VEGF may have significant potential against cerebral ischemia, partly by regulating the expression of MMPs.
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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 [53]
The Results and Discussion (page not supplied) report that VEGF inhibition reduced MMP-2 and MMP-9 expression and increased occludin levels in ischemic rat brains. They do not report claudin-5 breakdown or establish that VEGF-mediated MMP expression causes it; claudin-5 is mentioned only as a protein that assembles with occludin. (LLM, conf=0.87)
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- Authors
- Zhang, H.-T., Zhang, P., Gao, Y., Li, C.-L., Wang, H.-J., Chen, L.-C., Feng, Y., Li, R.-Y., Li, Y.-L., & Jiang, C.-L.
- Affiliations
- Harbin Medical University (CN)
- Binzhou Medical University (CN)
- Venue
- Molecular Medicine Reports
- Publisher
- Spandidos Publications
- Published
- 2016-11-29
- Volume
- 15
- Issue
- 1
- Pages
- 57-64
- ISSN
- 1791-2997 (ISSN-L)
- 1791-3004
- PMC
- PMC5355683
- OpenAlex
- W2557533493
- Cited by
- 101
- References
- 33
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 8 · 2023: 4 · 2022: 9 · 2021: 21 · 2020: 11 · 2019: 10 · 2018: 15 · 2017: 4 · 2015: 1
- FWCI
- 5.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Molecular Medicine Reports (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81372700)
- Natural Science Foundation of Heilongjiang Province (D201279)
- 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 › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- VEGF inhibition, blood-brain barrier disruption, acute cerebral ischemia, ischemic stroke, MMP-2, MMP-9, occludin, type IV collagen, middle cerebral artery occlusion, cerebral edema, blood-brain barrier permeability, infarct size, neurological outcome, microvessel density
- MeSH terms
- Animals, Blood-Brain Barrier, Brain, Brain Edema, Male, Rats, Sprague-Dawley, Neuroprotective Agents, Infarction, Middle Cerebral Artery, Matrix Metalloproteinases, Vascular Endothelial Growth Factor A, Antibodies, Neutralizing
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