title: 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-mediated control of gap junctions, and PAI-1 expression.
authors.affiliation: Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology at Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
authors.forename: Lizhen
authors.initials: L
authors.lastname: Li
authors.forename: Andrea
authors.initials: A
authors.lastname: Lundkvist
authors.forename: Daniel
authors.initials: D
authors.lastname: Andersson
authors.forename: Ulrika
authors.initials: U
authors.lastname: Wilhelmsson
authors.forename: Nobuo
authors.initials: N
authors.lastname: Nagai
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Pardo
authors.forename: Christina
authors.initials: C
authors.lastname: Nodin
authors.forename: Anders
authors.initials: A
authors.lastname: Ståhlberg
authors.forename: Karina
authors.initials: K
authors.lastname: Aprico
authors.forename: Kerstin
authors.initials: K
authors.lastname: Larsson
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yabe
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
authors.forename: Andrew
authors.initials: A
authors.lastname: Fotheringham
authors.forename: Ioan
authors.initials: I
authors.lastname: Davies
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Joan P
authors.initials: JP
authors.lastname: Schwartz
authors.forename: Marcela
authors.initials: M
authors.lastname: Pekna
authors.forename: Mikael
authors.initials: M
authors.lastname: Kubista
authors.forename: Fredrik
authors.initials: F
authors.lastname: Blomstrand
authors.forename: Nicholas
authors.initials: N
authors.lastname: Maragakis
authors.forename: Michael
authors.initials: M
authors.lastname: Nilsson
authors.forename: Milos
authors.initials: M
authors.lastname: Pekny
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000502:physiology*; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D017629:Gap Junctions; D005904:Glial Fibrillary Acidic Protein / Q000172:deficiency; D018698:Glutamic Acid / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020768:Middle Cerebral Artery; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D044023:Receptor, Endothelin B / Q000032:analysis*; D014746:Vimentin / Q000172:deficiency
chemical_list: D005904:Glial Fibrillary Acidic Protein; D017395:Plasminogen Activator Inhibitor 1; D044023:Receptor, Endothelin B; D014746:Vimentin; D018698:Glutamic Acid