title: Partial loss of VE-cadherin improves long-term outcome and cerebral blood flow after transient brain ischemia in mice.
abstract: BACKGROUND
  VE-cadherin is the chief constituent of endothelial adherens junctions. However, the role of VE-cadherin in the pathogenesis of cerebrovascular diseases including brain ischemia has not yet been investigated.
  
  
  METHODS
  VE-cadherin heterozygous (VEC(+/-)) mice and wildtype controls were subjected to transient brain ischemia by 30 min filamentous middle cerebral artery occlusion (MCAo)/reperfusion.
  
  
  RESULTS
  Acute lesion sizes as assessed by MR-imaging on day 3 did not differ between genotypes. Unexpectedly, however, partial loss of VE-cadherin resulted in long-term stroke protection measured histologically on day 28. Equally surprisingly, VEC(+/-) mice displayed no differences in post-stroke angiogenesis compared to littermate controls, but showed increased absolute regional cerebral blood flow in ischemic striatum at four weeks. The early induction of VE-cadherin mRNA transcription after stroke was reduced in VEC(+/-) mice. By contrast, N-cadherin and β-catenin mRNA expression showed a delayed, but sustained, upregulation up to 28 days after MCAo, which was increased in VEC(+/-) mice. Furthermore, partial loss of VE-cadherin resulted in a pattern of elevated ischemia-triggered mRNA transcription of pericyte-related molecules α-smooth muscle actin (α-SMA), aminopeptidase N (CD13), and platelet-derived growth factor receptor β (PDGFR-β).
  
  
  CONCLUSIONS
  Partial loss of VE-cadherin results in long term stroke protection. On the cellular and molecular level, this effect appears to be mediated by improved endothelial/pericyte interactions and the resultant increase in cerebral blood flow. Our study reinforces accumulating evidence that long-term stroke outcome depends critically on vascular mechanisms.
authors.affiliation: Klinik und Hochschulambulanz für Neurologie, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. karen.gertz@charite.de.|Center for Stroke Research Berlin (CSB), Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. karen.gertz@charite.de.
authors.forename: Karen
authors.initials: K
authors.lastname: Gertz
authors.affiliation: Center for Stroke Research Berlin (CSB), Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.|Klinik und Hochschulambulanz für Psychiatrie und Psychotherapie, Charité Universitätsmedizin Berlin, Charité Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany.
authors.forename: Golo
authors.initials: G
authors.lastname: Kronenberg
authors.affiliation: Klinik und Hochschulambulanz für Neurologie, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.|Center for Stroke Research Berlin (CSB), Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
authors.forename: Ria
authors.initials: R
authors.lastname: Uhlemann
authors.affiliation: Klinik für Neurochirurgie, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Vincent
authors.initials: V
authors.lastname: Prinz
authors.affiliation: Klinik und Hochschulambulanz für Neurologie, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
authors.forename: Ruben
authors.initials: R
authors.lastname: Marquina
authors.affiliation: IFOM, FIRC institute of Molecular Oncology, Via Adamello 16, 20139, Milan, Italy.|Department of Biosciences, University of Milan, Via Celoria 26, 20133, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Corada
authors.affiliation: IFOM, FIRC institute of Molecular Oncology, Via Adamello 16, 20139, Milan, Italy.|Department of Biosciences, University of Milan, Via Celoria 26, 20133, Milan, Italy.|Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 75185, Uppsala, Sweden.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
authors.affiliation: Klinik und Hochschulambulanz für Neurologie, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.|Center for Stroke Research Berlin (CSB), Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.|Excellence Cluster NeuroCure, Charitéplatz 1, 10117, Berlin, Germany.|German Center for Neurodegenerative Disease (DZNE), Charitéplatz 1, 10117, Berlin, Germany.|German Centre for Cardiovascular Research (DZHK), Charitéplatz 1, 10117, Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Endres
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D002546:Ischemic Attack, Transient / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020286:Pericytes / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D000099152:Cadherin 5
keywords: Adhesion molecule; Angiogenesis; Cerebral ischemia; Endothelium; Pericyte; Stroke