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Hyperfibrinolysis increases blood brain barrier permeability by a plasmin and bradykinin-dependent mechanism

Oscar A. Marcos-Contreras, Sara Martinez de Lizarrondo, Isabelle Bardou, Cyrille Orset, Mathilde Pruvost, Antoine Anfray, Yvann Frigout, Yannick Hommet, Laurent Lebouvier, Joan Montaner, Denis Vivien and Maxime Gauberti

Key points

  • Hydrodynamic transfection of plasmids encoding for plasminogen activators leads to a hyperfibrinolytic state in mice.

  • Hyperfibrinolysis increases blood brain barrier permeability by a plasmin and bradykinin-dependent mechanism.

Abstract

Hyperfibrinolysis is a systemic condition occurring in various clinical disorders such as trauma, liver cirrhosis or leukemia. Apart from increased bleeding tendency, the pathophysiological consequences of hyperfibrinolysis remain largely unknown. Our present aim was to develop an experimental model of hyperfibrinolysis and to study its effects on the homeostasis of the blood brain barrier (BBB). We induced a sustained hyperfibrinolytic state in mice by hydrodynamic transfection of a plasmid encoding for tissue-type plasminogen activator (tPA). As revealed by near-infrared fluorescence imaging, hyperfibrinolytic mice presented a significant increase in BBB permeability. Using a set of deletion variants of tPA and pharmacological approaches, we demonstrated that this effect was independent of N-Methyl-D-Aspartate Receptor (NMDA), Low density Lipoprotein related protein (LRP), protease activated receptor-1 (PAR-1) or matrix-metalloproteinases (MMPs). In contrast, we provide evidence that hyperfibrinolysis-induced BBB leakage is dependent on plasmin-mediated generation of bradykinin and subsequent activation of bradykinin B2 receptors. Accordingly, this effect was prevented by Icatibant, a clinically available B2 receptor antagonist. In agreement with these preclinical data, bradykinin generation was also observed in Humans in a context of acute pharmacological hyperfibrinolysis. Altogether, these results suggest that B2 receptors blockade may be a promising strategy to prevent the deleterious effects of hyperfibrinolysis on the homeostasis of the BBB.

  • Submitted March 16, 2016.
  • Accepted August 6, 2016.