Protective role of reactive astrocytes in brain ischemia.
Journal article, 2008
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-mediated control of gap junctions, and PAI-1 expression.
Glial Fibrillary Acidic Protein
Vimentin
Mice
Glutamic Acid
pathology
metabolism
Astrocytes
deficiency
Animals
Endothelin B
Brain Ischemia
analysis
Middle Cerebral Artery
metabolism
genetics
deficiency
Plasminogen Activator Inhibitor 1
physiology
Mice
Knockout
Gap Junctions
pathology
Receptor
Author
Lizhen Li
University of Gothenburg
Andrea Lundkvist
University of Gothenburg
Daniel Andersson
University of Gothenburg
Ulrika Wilhelmsson
University of Gothenburg
Nobuo Nagai
KU Leuven
Andrea C Pardo
Johns Hopkins University
Christina Nodin
University of Gothenburg
Anders Ståhlberg
Chalmers, Chemical and Biological Engineering
Karina Aprico
University of Gothenburg
Kerstin Larsson
University of Gothenburg
Takeshi Yabe
National Institute of Neurological Disorders and Stroke
Lieve Moons
KU Leuven
Andrew Fotheringham
University of Manchester
Ioan Davies
University of Manchester
Peter Carmeliet
KU Leuven
Joan P Schwartz
National Institute of Neurological Disorders and Stroke
Marcela Pekna
University of Gothenburg
Mikael Kubista
Chalmers, Chemical and Biological Engineering, Molecular Imaging
Fredrik Blomstrand
University of Gothenburg
Nicholas Maragakis
Johns Hopkins University
Michael Nilsson
University of Gothenburg
Milos Pekny
University of Gothenburg
Journal of Cerebral Blood Flow and Metabolism
0271-678X (ISSN)
Vol. 28 3 468-81Subject Categories
MEDICAL AND HEALTH SCIENCES
DOI
10.1038/sj.jcbfm.9600546
PubMed
17726492