title: Vascular signal transducer and activator of transcription-3 promotes angiogenesis and neuroplasticity long-term after stroke.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: From Center for Stroke Research Berlin (C.J.H., U.H., A.R., U.G., G.L-T., U.D., M.E., C.H.) and Department of Neurology (C.J.H., U.H., M.E., C.H.), Charité-Universitätsmedizin Berlin, Germany; Max-Delbrück Center for Molecular Medicine, Berlin, Germany (F.S., S.A.W., H.K.); Institute of Clinical Neurobiology, University Hospital, University of Würzburg, Germany (M.S.); Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Germany (H.K., U.D., M.E.); and German Center for Neurodegenerative Diseases (U.D., M.E.) and German Center for Cardiovascular Diseases (U.D., M.E.), Partner Site, Berlin, Germany.
authors: Christian J
authors: CJ
authors: Hoffmann
authors: From Center for Stroke Research Berlin (C.J.H., U.H., A.R., U.G., G.L-T., U.D., M.E., C.H.) and Department of Neurology (C.J.H., U.H., M.E., C.H.), Charité-Universitätsmedizin Berlin, Germany; Max-Delbrück Center for Molecular Medicine, Berlin, Germany (F.S., S.A.W., H.K.); Institute of Clinical Neurobiology, University Hospital, University of Würzburg, Germany (M.S.); Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Germany (H.K., U.D., M.E.); and German Center for Neurodegenerative Diseases (U.D., M.E.) and German Center for Cardiovascular Diseases (U.D., M.E.), Partner Site, Berlin, Germany.
authors: Ulrike
authors: U
authors: Harms
authors: From Center for Stroke Research Berlin (C.J.H., U.H., A.R., U.G., G.L-T., U.D., M.E., C.H.) and Department of Neurology (C.J.H., U.H., M.E., C.H.), Charité-Universitätsmedizin Berlin, Germany; Max-Delbrück Center for Molecular Medicine, Berlin, Germany (F.S., S.A.W., H.K.); Institute of Clinical Neurobiology, University Hospital, University of Würzburg, Germany (M.S.); Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Germany (H.K., U.D., M.E.); and German Center for Neurodegenerative Diseases (U.D., M.E.) and German Center for Cardiovascular Diseases (U.D., M.E.), Partner Site, Berlin, Germany.
authors: Andre
authors: A
authors: Rex
authors: From Center for Stroke Research Berlin (C.J.H., U.H., A.R., U.G., G.L-T., U.D., M.E., C.H.) and Department of Neurology (C.J.H., U.H., M.E., C.H.), Charité-Universitätsmedizin Berlin, Germany; Max-Delbrück Center for Molecular Medicine, Berlin, Germany (F.S., S.A.W., H.K.); Institute of Clinical Neurobiology, University Hospital, University of Würzburg, Germany (M.S.); Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Germany (H.K., U.D., M.E.); and German Center for Neurodegenerative Diseases (U.D., M.E.) and German Center for Cardiovascular Diseases (U.D., M.E.), Partner Site, Berlin, Germany.
authors: Frank
authors: F
authors: Szulzewsky
authors: From Center for Stroke Research Berlin (C.J.H., U.H., A.R., U.G., G.L-T., U.D., M.E., C.H.) and Department of Neurology (C.J.H., U.H., M.E., C.H.), Charité-Universitätsmedizin Berlin, Germany; Max-Delbrück Center for Molecular Medicine, Berlin, Germany (F.S., S.A.W., H.K.); Institute of Clinical Neurobiology, University Hospital, University of Würzburg, Germany (M.S.); Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Germany (H.K., U.D., M.E.); and German Center for Neurodegenerative Diseases (U.D., M.E.) and German Center for Cardiovascular Diseases (U.D., M.E.), Partner Site, Berlin, Germany.
authors: Susanne A
authors: SA
authors: Wolf
authors: From Center for Stroke Research Berlin (C.J.H., U.H., A.R., U.G., G.L-T., U.D., M.E., C.H.) and Department of Neurology (C.J.H., U.H., M.E., C.H.), Charité-Universitätsmedizin Berlin, Germany; Max-Delbrück Center for Molecular Medicine, Berlin, Germany (F.S., S.A.W., H.K.); Institute of Clinical Neurobiology, University Hospital, University of Würzburg, Germany (M.S.); Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Germany (H.K., U.D., M.E.); and German Center for Neurodegenerative Diseases (U.D., M.E.) and German Center for Cardiovascular Diseases (U.D., M.E.), Partner Site, Berlin, Germany.
authors: Ulrike
authors: U
authors: Grittner
authors: From Center for Stroke Research Berlin (C.J.H., U.H., A.R., U.G., G.L-T., U.D., M.E., C.H.) and Department of Neurology (C.J.H., U.H., M.E., C.H.), Charité-Universitätsmedizin Berlin, Germany; Max-Delbrück Center for Molecular Medicine, Berlin, Germany (F.S., S.A.W., H.K.); Institute of Clinical Neurobiology, University Hospital, University of Würzburg, Germany (M.S.); Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Germany (H.K., U.D., M.E.); and German Center for Neurodegenerative Diseases (U.D., M.E.) and German Center for Cardiovascular Diseases (U.D., M.E.), Partner Site, Berlin, Germany.
authors: Gisela
authors: G
authors: Lättig-Tünnemann
authors: From Center for Stroke Research Berlin (C.J.H., U.H., A.R., U.G., G.L-T., U.D., M.E., C.H.) and Department of Neurology (C.J.H., U.H., M.E., C.H.), Charité-Universitätsmedizin Berlin, Germany; Max-Delbrück Center for Molecular Medicine, Berlin, Germany (F.S., S.A.W., H.K.); Institute of Clinical Neurobiology, University Hospital, University of Würzburg, Germany (M.S.); Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Germany (H.K., U.D., M.E.); and German Center for Neurodegenerative Diseases (U.D., M.E.) and German Center for Cardiovascular Diseases (U.D., M.E.), Partner Site, Berlin, Germany.
authors: Michael
authors: M
authors: Sendtner
authors: From Center for Stroke Research Berlin (C.J.H., U.H., A.R., U.G., G.L-T., U.D., M.E., C.H.) and Department of Neurology (C.J.H., U.H., M.E., C.H.), Charité-Universitätsmedizin Berlin, Germany; Max-Delbrück Center for Molecular Medicine, Berlin, Germany (F.S., S.A.W., H.K.); Institute of Clinical Neurobiology, University Hospital, University of Würzburg, Germany (M.S.); Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Germany (H.K., U.D., M.E.); and German Center for Neurodegenerative Diseases (U.D., M.E.) and German Center for Cardiovascular Diseases (U.D., M.E.), Partner Site, Berlin, Germany.
authors: Helmut
authors: H
authors: Kettenmann
authors: From Center for Stroke Research Berlin (C.J.H., U.H., A.R., U.G., G.L-T., U.D., M.E., C.H.) and Department of Neurology (C.J.H., U.H., M.E., C.H.), Charité-Universitätsmedizin Berlin, Germany; Max-Delbrück Center for Molecular Medicine, Berlin, Germany (F.S., S.A.W., H.K.); Institute of Clinical Neurobiology, University Hospital, University of Würzburg, Germany (M.S.); Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Germany (H.K., U.D., M.E.); and German Center for Neurodegenerative Diseases (U.D., M.E.) and German Center for Cardiovascular Diseases (U.D., M.E.), Partner Site, Berlin, Germany.
authors: Ulrich
authors: U
authors: Dirnagl
authors: From Center for Stroke Research Berlin (C.J.H., U.H., A.R., U.G., G.L-T., U.D., M.E., C.H.) and Department of Neurology (C.J.H., U.H., M.E., C.H.), Charité-Universitätsmedizin Berlin, Germany; Max-Delbrück Center for Molecular Medicine, Berlin, Germany (F.S., S.A.W., H.K.); Institute of Clinical Neurobiology, University Hospital, University of Würzburg, Germany (M.S.); Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Germany (H.K., U.D., M.E.); and German Center for Neurodegenerative Diseases (U.D., M.E.) and German Center for Cardiovascular Diseases (U.D., M.E.), Partner Site, Berlin, Germany.
authors: Matthias
authors: M
authors: Endres
authors: From Center for Stroke Research Berlin (C.J.H., U.H., A.R., U.G., G.L-T., U.D., M.E., C.H.) and Department of Neurology (C.J.H., U.H., M.E., C.H.), Charité-Universitätsmedizin Berlin, Germany; Max-Delbrück Center for Molecular Medicine, Berlin, Germany (F.S., S.A.W., H.K.); Institute of Clinical Neurobiology, University Hospital, University of Würzburg, Germany (M.S.); Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Germany (H.K., U.D., M.E.); and German Center for Neurodegenerative Diseases (U.D., M.E.) and German Center for Cardiovascular Diseases (U.D., M.E.), Partner Site, Berlin, Germany. christoph.harms@charite.de.
authors: Christoph
authors: C
authors: Harms
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis / Q000235:genetics; D000071119:ADAMTS9 Protein; D000818:Animals; D001369:Axons / Q000502:physiology; D001921:Brain / Q000473:pathology; D060833:Cellular Microenvironment; D002560:Cerebrovascular Circulation; D003289:Convalescence; D004730:Endothelium, Vascular / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D020127:Recovery of Function; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016326:Extracellular Matrix Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; C545434:Adamts9 protein, mouse
keywords: angiogenesis effect; brain ischemia; endothelial cells; inflammation; microarray analysis