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Article Dans Une Revue European Heart Journal Année : 2013

Protective effects of angiopoietin-like 4 on cerebrovascular and functional damages in ischaemic stroke

Claire Bouleti
  • Fonction : Auteur
Thomas Mathivet
Berard Coqueran
  • Fonction : Auteur
Jean-Michel Serfaty
  • Fonction : Auteur
Mathieu Lesage
  • Fonction : Auteur
Elodie Berland
  • Fonction : Auteur
Corinne Ardidie-Robouant
  • Fonction : Auteur
Gilles Kauffenstein
  • Fonction : Auteur
Daniel Henrion
Bertrand Lapergue
  • Fonction : Auteur
Mikael Mazighi
Charles Duyckaerts
  • Fonction : Auteur
Gavin Thurston
  • Fonction : Auteur
David M. Valenzuela
  • Fonction : Auteur
Andrew J. Murphy
  • Fonction : Auteur
George D. Yancopoulos
  • Fonction : Auteur
Catherine Monnot
  • Fonction : Auteur
Isabelle Margaill
  • Fonction : Auteur

Résumé

AIMS: 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. METHODS AND 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. CONCLUSION: 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.

Dates et versions

hal-02142789 , version 1 (28-05-2019)

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Citer

Claire Bouleti, Thomas Mathivet, Berard Coqueran, Jean-Michel Serfaty, Mathieu Lesage, et al.. Protective effects of angiopoietin-like 4 on cerebrovascular and functional damages in ischaemic stroke. European Heart Journal, 2013, 34 (47), pp.3657--3668. ⟨10.1093/eurheartj/eht153⟩. ⟨hal-02142789⟩
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