Protective Role of Reactive Astrocytes in Brain Ischemia
Abstract
Reactive astrocytes are thought to protect the penumbra during brain ischemia, but direct evidence has been lacking due to the absence of suitable experimental models. Previously, we generated mice deficient in two intermediate filament (IF) proteins, glial fibrillary acidic protein (GFAP) and vimentin, whose upregulation is the hallmark of reactive astrocytes. GFAP(-/-)Vim(-/-) mice exhibit attenuated posttraumatic reactive gliosis, improved integration of neural grafts, and posttraumatic regeneration. Seven days after middle cerebral artery (MCA) transection, infarct volume was 210 to 350% higher in GFAP(-/-)Vim(-/-) than in wild-type (WT) mice; GFAP(-/-), Vim(-/-) and WT mice had the same infarct volume. Endothelin B receptor (ET(B)R) immunoreactivity was strong on cultured astrocytes and reactive astrocytes around infarct in WT mice but undetectable in GFAP(-/-)Vim(-/-) astrocytes. In WT astrocytes, ET(B)R colocalized extensively with bundles of IFs. GFAP(-/-)Vim(-/-) astrocytes showed attenuated endothelin-3-induced blockage of gap junctions. Total and glutamate transporter-1 (GLT-1)-mediated glutamate transport was lower in GFAP(-/-)Vim(-/-) than in WT mice. DNA array analysis and quantitative real-time PCR showed downregulation of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of tissue plasminogen activator. Thus, reactive astrocytes have a protective role in brain ischemia, and the absence of astrocyte IFs is linked to changes in glutamate transport, ET(B)R-…
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Attenuated reactive gliosis in Gfap−/−Vim−/− mice was connected with larger infarctions in focal brain ischemia and facilitated disease progression in Batten's disease.
“Attenuated reactive gliosis in Gfap−/− Vim−/− mice was connected with larger infarctions in a mouse model of focal brain ischemia (32) and facilitated disease progression in a mouse model of Batten's disease (33).”
From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [32]
The effects of acute central nervous system injury are comparable in Gfap−/−, Vim−/−, and wild-type mice.
“Further, the effects of acute central nervous system injury are comparable in Gfap−/−, Vim−/−, and wild-type mice (22, 32).”
From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [32]
GFAP and Vim are expressed at high levels in activated astrocytes and are critical for the activated phenotype.
“The intermediate filament proteins GFAP and Vim are expressed at high levels in activated astrocytes and are critical for the activated phenotype.”
From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [32]
Under baseline conditions, Gfap−/−Vim−/− mice have astrocytes of normal appearance and grossly normal brain anatomy.
“Under baseline conditions, however, Gfap−/−Vim−/− mice have astrocytes of normal appearance and grossly normal brain anatomy (22, 23, 32).”
From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [32]
When Gfap and Vim are both deleted, astrocytes cannot form intermediate filament networks or display reactive morphology.
“But when Gfap and Vim are both deleted, astrocytes cannot form intermediate filament networks or display reactive morphology (22, 23, 32).”
From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [32]
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- Authors
- Li, L., Lundkvist, A., Andersson, D., Wilhelmsson, U., Nagai, N., Pardo, A. C., Nodin, C., Ståhlberg, A., Aprico, K., Larsson, K., Yabe, T., Moons, L., Fotheringham, A., Davies, I., Carmeliet, P., Schwartz, J. P., Pekna, M., Kubista, M., Blomstrand, F., Maragakis, N., Nilsson, M., & Pekny, M.
- Affiliations
- University of Gothenburg (SE)
- KU Leuven (BE)
- Johns Hopkins University (US)
- Tataa Biocenter (Sweden) (SE)
- Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology at Sahlgrenska Academy, Göteborg University, Göteborg, Sweden
- National Institutes of Health (US)
- University of Manchester (GB)
- Corresponding author
- Pekny, Milos
- ORCID
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2007-08-29
- Volume
- 28
- Issue
- 3
- Pages
- 468-481
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- OpenAlex
- W1999495459
- Cited by
- 505
- References
- 43
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 19 · 2023: 23 · 2022: 19 · 2021: 31 · 2020: 24 · 2019: 34 · 2018: 34 · 2017: 30 · 2016: 34 · 2015: 35 · 2014: 46 · 2013: 28 · 2012: 35
- FWCI
- 13.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion)
- Chalmers Publication Library (Chalmers University of Technology) (submittedVersion)
- Chalmers Research (Chalmers University of Technology) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Keywords
- reactive astrocytes, cerebral ischemia, ischemic penumbra, glial fibrillary acidic protein, vimentin, intermediate filaments, endothelin B receptor, endothelin-3, gap junctions, GLT-1, glutamate uptake, plasminogen activator inhibitor-1, infarct size, middle cerebral artery occlusion, reactive gliosis
- MeSH terms
- Animals, Astrocytes, Brain Ischemia, Glial Fibrillary Acidic Protein, Vimentin, Plasminogen Activator Inhibitor 1, Gap Junctions, Mice, Knockout, Glutamic Acid, Middle Cerebral Artery, Receptor, Endothelin B, Mice
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