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.

Astrocytes

Endothelin B

deficiency

Mice

physiology

Knockout

Mice

Gap Junctions

analysis

Brain Ischemia

Glutamic Acid

Plasminogen Activator Inhibitor 1

Receptor

Glial Fibrillary Acidic Protein

Middle Cerebral Artery

metabolism

metabolism

pathology

Vimentin

Animals

deficiency

genetics

pathology

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 School of Medicine

Ioan Davies

University of Manchester School of Medicine

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 3 468-81

Subject Categories

MEDICAL AND HEALTH SCIENCES

DOI

10.1038/sj.jcbfm.9600546

PubMed

17726492

More information

Latest update

9/18/2018