Paul-Emile Labeyrie1, Romain Goulay1, Sara Martinez de Lizarrondo1, Marie Hébert1, Maxime Gauberti1, Eric Maubert1, Barbara Delaunay1, Benjamin Gory1, Francesco Signorelli1, Francis Turjman1, Emmanuel Touzé1, Patrick Courthéoux1, Denis Vivien2, Cyrille Orset1. 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.
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.
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