I ntracranial aneurysms (IAs) are brain vascular malformations, with a prevalence of 3% to 5% in the general population. 1-3 In most cases, IA causes no symptom and goes unnoticed. However, the rupture of an IA causes a subarachnoid hemorrhage leading to high mortality and disability rates. 3 Despite recent therapeutic advances, no reliable noninvasive treatment has proved efficient to prevent aneurysm growth and rupture. 4-6 Thus, a better understanding of the pathophysiology of IAs is

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... y to develop new preventive and therapeutic strategies. 2,6 Aneurysms originate from a series of events starting with the activation of endothelial cells leading to inflammatory processes and ultimately to a progressive loss of integrity of the arterial wall. 7-9 Some of the actors involved in this cascade of events have been identified, including macrophages, lymphocytes, and their effector molecules (like chemokines and inflammatory cytokines) 7,10,11 and matrix metalloproteinases (MMPs). 12 tPA (tissue-type plasminogen activator) is a serine protease expressed and released by endothelial cells, where it displays its fibrinolytic role through activation of plasminogen into plasmin. 13,14 Interestingly, an increased expression of tPA has been observed in aortic aneurysms. 15-18 Furthermore, the tPA-plasmin axis is well known to promote inflammatory 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.