Christian J Hoffmann1, Ulrike Harms1, Andre Rex1, Frank Szulzewsky1, Susanne A Wolf1, Ulrike Grittner1, Gisela Lättig-Tünnemann1, Michael Sendtner1, Helmut Kettenmann1, Ulrich Dirnagl1, Matthias Endres1, Christoph Harms2. 1. 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. 2. 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.
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. METHODS AND 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.
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. METHODS AND 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: Ping Sun; Kai Zhang; Sulaiman H Hassan; Xuejing Zhang; Xuelian Tang; Hongjian Pu; R Anne Stetler; Jun Chen; Ke-Jie Yin Journal: Circ Res Date: 2020-03-05 Impact factor: 17.367
Authors: Lars Winkler; Rosel Blasig; Olga Breitkreuz-Korff; Philipp Berndt; Sophie Dithmer; Hans C Helms; Dmytro Puchkov; Kavi Devraj; Mehmet Kaya; Zhihai Qin; Stefan Liebner; Hartwig Wolburg; Anuska V Andjelkovic; Andre Rex; Ingolf E Blasig; Reiner F Haseloff Journal: J Cereb Blood Flow Metab Date: 2020-02-13 Impact factor: 6.200
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