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Stroke. 2017 Sep;48(9):2574-2582. doi: 10.1161/STROKEAHA.117.017305. Epub 2017 Jul 28.

Vascular Tissue-Type Plasminogen Activator Promotes Intracranial Aneurysm Formation.

Author information

1
From the Department of Physiopathology and Imaging of Neurological Disorders, INSERM U1237, UNICAEN, GIP Cyceron, France (P.-E.L., R.G., S.M.d.L., M.H., M.G., E.M., B.D., E.T., P.C., D.V., C.O.); Department of Interventional Neuroradiology (P.-E.L., B.G., F.T.) and Department of Neurosurgery (F.S.), Hôpital Wertheimer, University Lyon 1, Bron, France; and Department of Neurology (E.T.), Department of Neuroradiology (P.C.), and Department of Clinical Research (D.V.), CHU Caen, University Caen Normandie, France.
2
From the Department of Physiopathology and Imaging of Neurological Disorders, INSERM U1237, UNICAEN, GIP Cyceron, France (P.-E.L., R.G., S.M.d.L., M.H., M.G., E.M., B.D., E.T., P.C., D.V., C.O.); Department of Interventional Neuroradiology (P.-E.L., B.G., F.T.) and Department of Neurosurgery (F.S.), Hôpital Wertheimer, University Lyon 1, Bron, France; and Department of Neurology (E.T.), Department of Neuroradiology (P.C.), and Department of Clinical Research (D.V.), CHU Caen, University Caen Normandie, France. vivien@cyceron.fr.

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.

KEYWORDS:

animals; intracranial aneurysm; mice; physiopathology; tissue plasminogen activator

PMID:
28754830
DOI:
10.1161/STROKEAHA.117.017305
[Indexed for MEDLINE]

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