Protective role of reactive astrocytes in brain ischemia.
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.
Li
Lizhen
L
Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology at Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
Lundkvist
Andrea
A
Andersson
Daniel
D
Wilhelmsson
Ulrika
U
Nagai
Nobuo
N
Pardo
Andrea C
AC
Nodin
Christina
C
Ståhlberg
Anders
A
Aprico
Karina
K
Larsson
Kerstin
K
Yabe
Takeshi
T
Moons
Lieve
L
Fotheringham
Andrew
A
Davies
Ioan
I
Carmeliet
Peter
P
Schwartz
Joan P
JP
Pekna
Marcela
M
Kubista
Mikael
M
Blomstrand
Fredrik
F
Maragakis
Nicholas
N
Nilsson
Michael
M
Pekny
Milos
M
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
D005904:Glial Fibrillary Acidic Protein; D017395:Plasminogen Activator Inhibitor 1; D044023:Receptor, Endothelin B; D014746:Vimentin; D018698:Glutamic Acid