title: 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, and leukemia. Apart from increased bleeding tendency, the pathophysiological consequences of hyperfibrinolysis remain largely unknown. Our 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, low-density lipoprotein-related protein, protease-activated receptor-1, or matrix metalloproteinases. 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 receptor blockade may be a promising strategy to prevent the deleterious effects of hyperfibrinolysis on the homeostasis of the BBB.
authors.affiliation: INSERM Unité 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Cyceron, Université de Caen Normandy (UNICAEN) Caen, France.
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Marcos-Contreras
authors.affiliation: INSERM Unité 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Cyceron, Université de Caen Normandy (UNICAEN) Caen, France.
authors.forename: Sara
authors.initials: S
authors.lastname: Martinez de Lizarrondo
authors.affiliation: INSERM Unité 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Cyceron, Université de Caen Normandy (UNICAEN) Caen, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bardou
authors.affiliation: INSERM Unité 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Cyceron, Université de Caen Normandy (UNICAEN) Caen, France.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Orset
authors.affiliation: INSERM Unité 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Cyceron, Université de Caen Normandy (UNICAEN) Caen, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Pruvost
authors.affiliation: INSERM Unité 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Cyceron, Université de Caen Normandy (UNICAEN) Caen, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Anfray
authors.affiliation: INSERM Unité 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Cyceron, Université de Caen Normandy (UNICAEN) Caen, France.
authors.forename: Yvann
authors.initials: Y
authors.lastname: Frigout
authors.affiliation: INSERM Unité 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Cyceron, Université de Caen Normandy (UNICAEN) Caen, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Hommet
authors.affiliation: INSERM Unité 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Cyceron, Université de Caen Normandy (UNICAEN) Caen, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Lebouvier
authors.affiliation: Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
authors.affiliation: INSERM Unité 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Cyceron, Université de Caen Normandy (UNICAEN) Caen, France.|Department of Cell Biology, and.
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
authors.affiliation: INSERM Unité 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Cyceron, Université de Caen Normandy (UNICAEN) Caen, France.|Department of Diagnostic Imaging and Interventional Radiology, Medical Center, Caen University Hospital, Caen, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Gauberti
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001920:Bradykinin / Q000378:metabolism / Q000502:physiology*; D065094:Bradykinin B2 Receptor Antagonists / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005341:Fibrinolysin / Q000378:metabolism / Q000502:physiology*; D005342:Fibrinolysis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D057446:Hydrodynamics; D051379:Mice; D008822:Mice, Transgenic; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: D065094:Bradykinin B2 Receptor Antagonists; D043782:Receptor, Bradykinin B2; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D001920:Bradykinin