Vascular signal transducer and activator of transcription-3 promotes angiogenesis and neuroplasticity long-term after stroke

Poststroke angiogenesis contributes to long-term recovery after stroke. Signal transducer and activator of transcription-3 (Stat3) is a key regulator for various inflammatory signals and angiogenesis. It was the aim of this study to determine its function in poststroke outcome. We generated a tamoxi...

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Bibliographic Details
Published in:Circulation (New York, N.Y.) N.Y.), 2015-05, Vol.131 (20), p.1772-1782
Main Authors: Hoffmann, Christian J, Harms, Ulrike, Rex, Andre, Szulzewsky, Frank, Wolf, Susanne A, Grittner, Ulrike, Lättig-Tünnemann, Gisela, Sendtner, Michael, Kettenmann, Helmut, Dirnagl, Ulrich, Endres, Matthias, Harms, Christoph
Format: Article
Language:English
Subjects:
ADAM Proteins - biosynthesis
ADAM Proteins - genetics
ADAMTS9 Protein
Animals
Axons - physiology
Brain - pathology
Cellular Microenvironment
Cerebrovascular Circulation
Convalescence
Endothelium, Vascular - metabolism
Extracellular Matrix Proteins - metabolism
Gene Expression Profiling
Infarction, Middle Cerebral Artery - pathology
Infarction, Middle Cerebral Artery - physiopathology
Mice
Mice, Knockout
Microglia - pathology
Neovascularization, Physiologic - physiology
Neuronal Plasticity - physiology
Oligonucleotide Array Sequence Analysis
Phosphorylation
Protein Processing, Post-Translational
Recovery of Function
Signal Transduction - physiology
STAT3 Transcription Factor - deficiency
STAT3 Transcription Factor - genetics
STAT3 Transcription Factor - physiology
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Summary:Poststroke angiogenesis contributes to long-term recovery after stroke. Signal transducer and activator of transcription-3 (Stat3) is a key regulator for various inflammatory signals and angiogenesis. It was the aim of this study to determine its function in poststroke outcome. We generated a tamoxifen-inducible and endothelial-specific Stat3 knockout mouse model by crossbreeding Stat3(floxed/KO) and Tie2-Cre(ERT2) mice. Cerebral ischemia was induced by 30 minutes of middle cerebral artery occlusion. We demonstrated that endothelial Stat3 ablation did not alter lesion size 2 days after ischemia but did worsen functional outcome at 14 days and increase lesion size at 28 days. At this late time point vascular Stat3 expression and phosphorylation were still increased in wild-type mice. Gene array analysis of a CD31-enriched cell population of the neurovascular niche showed that endothelial Stat3 ablation led to a shift toward an antiangiogenic and axon growth-inhibiting micromilieu after stroke, with an increased expression of Adamts9. Remodeling and glycosylation of the extracellular matrix and microglia proliferation were increased, whereas angiogenesis was reduced. Endothelial Stat3 regulates angiogenesis, axon growth, and extracellular matrix remodeling and is essential for long-term recovery after stroke. It might serve as a potent target for stroke treatment after the acute phase by fostering angiogenesis and neuroregeneration.
ISSN:0009-7322
1524-4539
DOI:10.1161/circulationaha.114.013003