Vascular Tissue-Type Plasminogen Activator Promotes Intracranial Aneurysm Formation.

Abstract:

BACKGROUND AND PURPOSE:Although the mechanisms that contribute to intracranial aneurysm (IA) formation and rupture are not totally elucidated, inflammation and matrix remodeling are incriminated. Because tPA (tissue-type plasminogen activator) controls both inflammatory and matrix remodeling processes, we hypothesized that tPA could be involved in the pathophysiology of IA. METHODS:Immunofluorescence analyses of tPA and its main substrate within the aneurysmal wall of murine and human samples were performed. We then compared the formation and rupture of IAs in wild-type, tPA-deficient and type 1 plasminogen activator inhibitor-deficient mice subjected to a model of elastase-induced IA. The specific contribution of vascular versus global tPA was investigated by performing hepatic hydrodynamic transfection of a cDNA encoding for tPA in tPA-deficient mice. The formation and rupture of IAs were monitored by magnetic resonance imaging tracking for 28 days. RESULTS:Immunofluorescence revealed increased expression of tPA within the aneurysmal wall. The number of aneurysms and their symptomatic ruptures were significantly lower in tPA-deficient than in wild-type mice. Conversely, they were higher in plasminogen activator inhibitor-deficient mice. The wild-type phenotype could be restored in tPA-deficient mice by selectively increasing circulating levels of tPA via hepatic hydrodynamic transfection of a cDNA encoding for tPA. CONCLUSIONS:Altogether, this preclinical study demonstrates that the tPA present in the blood stream is a key player of the formation of IAs. Thus, tPA should be considered as a possible new target for the prevention of IAs formation and rupture.

journal_name

Stroke

journal_title

Stroke

authors

Labeyrie PE,Goulay R,Martinez de Lizarrondo S,Hébert M,Gauberti M,Maubert E,Delaunay B,Gory B,Signorelli F,Turjman F,Touzé E,Courthéoux P,Vivien D,Orset C

doi

10.1161/STROKEAHA.117.017305

subject

Has Abstract

pub_date

2017-09-01 00:00:00

pages

2574-2582

issue

9

eissn

0039-2499

issn

1524-4628

pii

STROKEAHA.117.017305

journal_volume

48

pub_type

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