title: EphrinB2 Activation Enhances Vascular Repair Mechanisms and Reduces Brain Swelling After Mild Cerebral Ischemia.
abstract: Cerebral edema caused by the disruption of the blood-brain barrier is a major complication after stroke. Therefore, strategies to accelerate and enhance neurovascular recovery after stroke are of prime interest. Our main aim was to study the role of ephrinB2/EphB4 signaling in mediating the vascular repair and in blood-brain barrier restoration after mild cerebral ischemia occlusion/reperfusion.
  
  
  
  Here, we show that the guidance molecule ephrinB2 plays a key role in neurovascular protection and blood-brain barrier restoration after stroke. In a focal stroke model, we characterize the stroke-induced damage to cerebral blood vessels and their subsequent endogenous repair on a cellular, molecular, and functional level. EphrinB2 and its tyrosine kinase receptor EphB4 are upregulated early after stroke by endothelial cells and perivascular support cells, in parallel to their reassembly during neurovascular recovery. Using both retroviral and pharmacological approaches, we show that the inhibition of ephrinB2/EphB4 signaling suppresses post-middle cerebral artery occlusion neurovascular repair mechanisms resulting in an aggravation of brain swelling. In contrast, the activation of ephrinB2 after brain ischemia leads to an increased pericyte recruitment and increased endothelial-pericyte interaction, resulting in an accelerated neurovascular repair after ischemia.
  
  
  
  We show that reducing swelling could result in improved outcome because of reduction in damaged brain tissue. We also identify a novel role for ephrinB2/EphB4 signaling in the maintenance of the neurovascular homeostasis and provide a novel therapeutic approach in reducing brain swelling after stroke.
authors.affiliation: From the Department of Neurosurgery (A.G., F.B.F., M.N.-K., I.K., P.V.), Center for Stroke Research (K.G., M.E., P.V.), Department of Neurology (M.E.), and German Center for Neurodegenerative Diseases (M.E.), Charité, Universitätsmedizin Berlin, Germany; German Center for Cardiovascular Research (DZHK), Max-Delbrück-Centrum Für Molekulare Medizin Berlin-Buch, Germany (M.E.); and Freie Universität Berlin, Germany (A.G.).
authors.forename: Adnan
authors.initials: A
authors.lastname: Ghori
authors.affiliation: From the Department of Neurosurgery (A.G., F.B.F., M.N.-K., I.K., P.V.), Center for Stroke Research (K.G., M.E., P.V.), Department of Neurology (M.E.), and German Center for Neurodegenerative Diseases (M.E.), Charité, Universitätsmedizin Berlin, Germany; German Center for Cardiovascular Research (DZHK), Max-Delbrück-Centrum Für Molekulare Medizin Berlin-Buch, Germany (M.E.); and Freie Universität Berlin, Germany (A.G.).
authors.forename: Florian B
authors.initials: FB
authors.lastname: Freimann
authors.affiliation: From the Department of Neurosurgery (A.G., F.B.F., M.N.-K., I.K., P.V.), Center for Stroke Research (K.G., M.E., P.V.), Department of Neurology (M.E.), and German Center for Neurodegenerative Diseases (M.E.), Charité, Universitätsmedizin Berlin, Germany; German Center for Cardiovascular Research (DZHK), Max-Delbrück-Centrum Für Molekulare Medizin Berlin-Buch, Germany (M.E.); and Freie Universität Berlin, Germany (A.G.).
authors.forename: Melina
authors.initials: M
authors.lastname: Nieminen-Kelhä
authors.affiliation: From the Department of Neurosurgery (A.G., F.B.F., M.N.-K., I.K., P.V.), Center for Stroke Research (K.G., M.E., P.V.), Department of Neurology (M.E.), and German Center for Neurodegenerative Diseases (M.E.), Charité, Universitätsmedizin Berlin, Germany; German Center for Cardiovascular Research (DZHK), Max-Delbrück-Centrum Für Molekulare Medizin Berlin-Buch, Germany (M.E.); and Freie Universität Berlin, Germany (A.G.).
authors.forename: Irina
authors.initials: I
authors.lastname: Kremenetskaia
authors.affiliation: From the Department of Neurosurgery (A.G., F.B.F., M.N.-K., I.K., P.V.), Center for Stroke Research (K.G., M.E., P.V.), Department of Neurology (M.E.), and German Center for Neurodegenerative Diseases (M.E.), Charité, Universitätsmedizin Berlin, Germany; German Center for Cardiovascular Research (DZHK), Max-Delbrück-Centrum Für Molekulare Medizin Berlin-Buch, Germany (M.E.); and Freie Universität Berlin, Germany (A.G.).
authors.forename: Karen
authors.initials: K
authors.lastname: Gertz
authors.affiliation: From the Department of Neurosurgery (A.G., F.B.F., M.N.-K., I.K., P.V.), Center for Stroke Research (K.G., M.E., P.V.), Department of Neurology (M.E.), and German Center for Neurodegenerative Diseases (M.E.), Charité, Universitätsmedizin Berlin, Germany; German Center for Cardiovascular Research (DZHK), Max-Delbrück-Centrum Für Molekulare Medizin Berlin-Buch, Germany (M.E.); and Freie Universität Berlin, Germany (A.G.).
authors.forename: Matthias
authors.initials: M
authors.lastname: Endres
authors.affiliation: From the Department of Neurosurgery (A.G., F.B.F., M.N.-K., I.K., P.V.), Center for Stroke Research (K.G., M.E., P.V.), Department of Neurology (M.E.), and German Center for Neurodegenerative Diseases (M.E.), Charité, Universitätsmedizin Berlin, Germany; German Center for Cardiovascular Research (DZHK), Max-Delbrück-Centrum Für Molekulare Medizin Berlin-Buch, Germany (M.E.); and Freie Universität Berlin, Germany (A.G.). peter.vajkoczy@charite.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Vajkoczy
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002460:Cell Line; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D036388:Ephrin-B2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D034622:RNA Interference; D036224:Receptor, EphB4 / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection
chemical_list: C000601240:EFNB2 protein, mouse; D036388:Ephrin-B2; D018696:Neuroprotective Agents; C086681:Ephb4 protein, mouse; D036224:Receptor, EphB4
keywords: blood–brain barrier; brain edema; brain ischemia; endothelial cells; homeostasis