Preserved vascular integrity and enhanced survival following neuropilin-1 inhibition in a mouse model of CD8 T cell-initiated CNS vascular permeability
Open accessAbstract
BACKGROUND: Altered permeability of the blood-brain barrier (BBB) is a feature of numerous neurological conditions including multiple sclerosis, cerebral malaria, viral hemorrhagic fevers and acute hemorrhagic leukoencephalitis. Our laboratory has developed a murine model of CD8 T cell-initiated central nervous system (CNS) vascular permeability in which vascular endothelial growth factor (VEGF) signaling plays a prominent role in BBB disruption. FINDINGS: In this study, we addressed the hypothesis that in vivo blockade of VEGF signal transduction through administration of peptide (ATWLPPR) to inhibit neuropilin-1 (NRP-1) would have a therapeutic effect following induction of CD8 T cell-initiated BBB disruption. We report that inhibition of NRP-1, a co-receptor that enhances VEGFR2 (flk-1) receptor activation, decreases vascular permeability, brain hemorrhage, and mortality in this model of CD8 T cell-initiated BBB disruption. We also examine the expression pattern of VEGFR2 (flk-1) and VEGFR1 (flt-1) mRNA expression during a time course of this condition. We find that viral infection of the brain leads to increased expression of flk-1 mRNA. In addition, flk-1 and flt-1 expression levels decrease in the striatum and hippocampus in later time points following induction of CD8 T cell-mediated BBB disruption. CONCLUSION: This study demonstrates that NRP-1 is a potential therapeutic target in neuro-inflammatory diseases involving BBB disruption and brain hemorrhage. Additionally, the reduction in VEGF receptors subsequent to BBB disruption could be involved in compensatory negative feedback as an attempt to reduce vascular permeability.
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Neuropilin is required for guidance of tip cells during sprouting angiogenesis, by balancing pro-angiogenic and anti-angiogenic signals between major pathways including VEGF, semaphorins and Wnt signaling; its upregulation in vessels contributes to BBB breakdown during brain injury and inflammation.
“Neuropilin, a common co-receptor and regulator of many morphogens and growth factors, is required for guidance of tip cells during spouting angiogenesis (127), by balancing the pro-angiogenic and anti-angiogenic signals between major pathways including VEGF, semaphorins and Wnt signaling; its upregulation in vessels contributes to BBB breakdown during brain injury and inflammation (564, 679).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [564]
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Research works printed but not linked: 19
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Blood-Brain Barrier: From Physiology to Disease and Back
Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., & Zlokovic, B. V. (2019) · Physiological Reviews · doi:10.1152/physrev.00050.2017 · Cited by 2,294 · see citing works
A perspective on the role of class III semaphorin signaling in central nervous system trauma
Mecollari, V., Nieuwenhuis, B., & Verhaagen, J. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00328 · Cited by 79 · see citing works
- Authors
- Suidan, G. L., Dickerson, J. W., Johnson, H. L., Chan, T. W., Pavelko, K. D., Pirko, I., Seroogy, K. B., & Johnson, A. J.
- Affiliations
- University of Cincinnati (US)
- Mayo Clinic (US)
- Corresponding author
- Suidan, Georgette L
- Dickerson, Jonathan W
- Johnson, Aaron J
- ORCID
- Venue
- Journal of Neuroinflammation
- Published
- 2012-09-18
- Volume
- 9
- Issue
- 1
- Pages
- 218-218
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC3489603
- OpenAlex
- W2156232409
- Cited by
- 19
- References
- 0
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 1 · 2016: 3 · 2015: 1 · 2014: 1 · 2013: 2
- FWCI
- 0.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (T35DK060444)
- National Institute of Neurological Disorders and Stroke (NS-060881, R01NS060881)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- neuropilin-1, VEGF signaling, blood-brain barrier permeability, cerebral hemorrhage, neuroinflammation, VEGF receptor expression, mouse model
- MeSH terms
- Animals, Capillary Permeability, Cell Survival, Central Nervous System, Mice, Inbred C57BL, Peptides, RNA, Messenger, CD8-Positive T-Lymphocytes, Models, Animal, Neuropilin-1, Vascular Endothelial Growth Factor Receptor-1, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factor A, Mice
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