title: Protective effects of angiopoietin-like 4 on cerebrovascular and functional damages in ischaemic stroke.
abstract: OBJECTIVE
  Given the impact of vascular injuries and oedema on brain damage caused during stroke, vascular protection represents a major medical need. We hypothesized that angiopoietin-like 4 (ANGPTL4), a regulator of endothelial barrier integrity, might exert a protective effect during ischaemic stroke.
  
  
  RESULTS
  Using a murine transient ischaemic stroke model, treatment with recombinant ANGPTL4 led to significantly decreased infarct size and improved behaviour. Quantitative characteristics of the vascular network (density and branchpoints) were preserved in ANGPTL4-treated mice. Integrity of tight and adherens junctions was also quantified and ANGPTL4-treated mice displayed increased VE-cadherin and claudin-5-positive areas. Brain oedema was thus significantly decreased in ANGPTL4-treated mice. In accordance, vascular damage and infarct severity were increased in angptl4-deficient mice thus providing genetic evidence that ANGPTL4 preserves brain tissue from ischaemia-induced alterations. Altogether, these data show that ANGPTL4 protects not only the global vascular network, but also interendothelial junctions and controls both deleterious inflammatory response and oedema. Mechanistically, ANGPTL4 counteracted VEGF signalling and thereby diminished Src-signalling downstream from VEGFR2. This led to decreased VEGFR2-VE-cadherin complex disruption, increased stability of junctions and thus increased endothelial cell barrier integrity of the cerebral microcirculation. In addition, ANGPTL4 prevented neuronal loss in the ischaemic area.
  
  
  CONCLUSIONS
  These results, therefore, show ANGPTL4 counteracts the loss of vascular integrity in ischaemic stroke, by restricting Src kinase signalling downstream from VEGFR2. ANGPTL4 treatment thus reduces oedema, infarct size, neuronal loss, and improves mice behaviour. These results suggest that ANGPTL4 constitutes a relevant target for vasculoprotection and cerebral protection during stroke.
authors.affiliation: Collège de France, Center for Interdisciplinary Research in Biology (CIRB), 11, place Marcelin Berthelot, Paris F-75005, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Bouleti
authors.forename: Thomas
authors.initials: T
authors.lastname: Mathivet
authors.forename: Berard
authors.initials: B
authors.lastname: Coqueran
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Serfaty
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lesage
authors.forename: Elodie
authors.initials: E
authors.lastname: Berland
authors.forename: Corinne
authors.initials: C
authors.lastname: Ardidie-Robouant
authors.forename: Gilles
authors.initials: G
authors.lastname: Kauffenstein
authors.forename: Daniel
authors.initials: D
authors.lastname: Henrion
authors.forename: Bertrand
authors.initials: B
authors.lastname: Lapergue
authors.forename: Mikael
authors.initials: M
authors.lastname: Mazighi
authors.forename: Charles
authors.initials: C
authors.lastname: Duyckaerts
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.forename: David M
authors.initials: DM
authors.lastname: Valenzuela
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: Catherine
authors.initials: C
authors.lastname: Monnot
authors.forename: Isabelle
authors.initials: I
authors.lastname: Margaill
authors.forename: Stephane
authors.initials: S
authors.lastname: Germain
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000172:deficiency / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000098:blood supply; D001929:Brain Edema / Q000517:prevention & control; D002545:Brain Ischemia / Q000503:physiopathology / Q000517:prevention & control*; D015820:Cadherins / Q000502:physiology; D002463:Cell Membrane Permeability / Q000187:drug effects; D004660:Encephalitis / Q000503:physiopathology; D042783:Endothelial Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018697:Nootropic Agents / Q000494:pharmacology*; D020521:Stroke / Q000503:physiopathology / Q000517:prevention & control*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology; D019061:src-Family Kinases / Q000502:physiology
chemical_list: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D015820:Cadherins; D018697:Nootropic Agents; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D019061:src-Family Kinases
keywords: Acute cerebral infarction; Angiogenesis; Endothelium; Hypoxia; Ischaemia; Vascular biology