Epileptiform activity induces vascular remodeling and zonula occludens 1 downregulation in organotypic hippocampal cultures: role of VEGF signaling pathways
Open accessAbstract
Recent studies suggest that blood-brain barrier (BBB) permeability contributes to epileptogenesis in symptomatic epilepsies. We have previously described angiogenesis, aberrant vascularization, and BBB alteration in drug-refractory temporal lobe epilepsy. Here, we investigated the role of vascular endothelial growth factor (VEGF) in an in vitro integrative model of vascular remodeling induced by epileptiform activity in rat organotypic hippocampal cultures. After kainate-induced seizure-like events (SLEs), we observed an overexpression of VEGF and VEGF receptor-2 (VEGFR-2) as well as receptor activation. Vascular density and branching were significantly increased, whereas zonula occludens 1 (ZO-1), a key protein of tight junctions (TJs), was downregulated. These effects were fully prevented by VEGF neutralization. Using selective inhibitors of VEGFR-2 signaling pathways, we found that phosphatidylinositol 3-kinase is involved in cell survival, protein kinase C (PKC) in vascularization, and Src in ZO-1 regulation. Recombinant VEGF reproduced the kainate-induced vascular changes. As in the kainate model, VEGFR-2 and Src were involved in ZO-1 downregulation. These results showed that VEGF/VEGFR-2 initiates the vascular remodeling induced by SLEs and pointed out the roles of PKC in vascularization and Src in TJ dysfunction, respectively. This suggests that Src pathway could be a therapeutic target for BBB protection in epilepsies.
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Microglial and astrocytic IL-1β act directly on the endothelium, altering BBB permeability and contributing to epileptogenesis.
“Microglial and astrocytic IL-1β act directly on the endothelium, altering BBB permeability and contributing to epileptogenesis.”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Morin-Brureau et al., 2011
The interaction between microglia and ECs is important in epilepsy.
“These studies further suggest the importance of the interaction between microglia and ECs in epilepsy.”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Morin-Brureau et al., 2011
IL-1R1 activation on ECs increases BBB permeability through downregulation of tight junction proteins, mainly ZO-1, and upregulation of NO and MMPs.
“IL-1R1 activation on ECs increases BBB permeability through downregulation of tight junction proteins, mainly ZO-1, and upregulation of NO and MMPs (Ravizza et al., 2008a,b; Morin-Brureau et al., 2011; Librizzi et al., 2012).”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Morin-Brureau et al., 2011
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References 62 · Cited by 159
- Authors
- Morin-Brureau, M., Lebrun, A., Rousset, M.-C., Fagni, L., Bockaert, J., de Bock, F., & Lerner-Natoli, M.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-07-20
- Volume
- 31
- Issue
- 29
- Pages
- 10677-10688
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6622643
- OpenAlex
- W2022120753
- Cited by
- 159
- References
- 62
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 11 · 2023: 7 · 2022: 8 · 2021: 7 · 2020: 15 · 2019: 7 · 2018: 17 · 2017: 12 · 2016: 9 · 2015: 14 · 2014: 16 · 2013: 9 · 2012: 14
- FWCI
- 7.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- epileptiform activity, vascular remodeling, zonula occludens-1, blood-brain barrier permeability, VEGF signaling, VEGFR2, tight junction dysfunction, kainate-induced seizures, organotypic hippocampal slice cultures, phosphatidylinositol 3-kinase, protein kinase C, Src kinase, angiogenesis, epileptogenesis
- MeSH terms
- Anesthetics, Local, Animals, Animals, Newborn, Antibodies, Drug Interactions, Endothelium, Vascular, Hippocampus, Kainic Acid, L-Lactate Dehydrogenase, Membrane Proteins, Nerve Tissue Proteins, Organ Culture Techniques, Phosphoproteins, Propidium, Teprotide, Tetrodotoxin, Time Factors, Signal Transduction, Down-Regulation, Rats, Sprague-Dawley, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factor A, Rats, Brain Waves, Zonula Occludens-1 Protein
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