Background : Intracranial aneurysm (IA) is an arterial disease resulting in abnormal enlargement of the vessel lumen. Most IAs are asymptomatic but their rupture induces subarachnoid hemorrhage with 24% resulting in death and 11% in severe disability. Occlusion of an unruptured IA by microsurgical or endovascular treatment results in a procedural morbidity and mortality of between 4 to 7%. Decision making between "intervention" or "continuing observation" for an individual patient is currently based on clinical scores and further supported by radiologic imaging of IA characteristics including the observation of vessel wall enhancement (VWE) on magnetic resonance imaging (MRI). VWE reflects a local accumulation of colloid contrast agent, which has been associated with IA wall instability. The pathophysiology of VWE is unknown but enhanced permeability of arterial endothelium, excessive macrophage infiltration, or presence of vasa vasorum have been proposed as potential mechanisms.

Purpose : The goal of our study is to investigate the expression of tight junction (TJ) proteins in the arterial endothelium of human IA domes in the context of IA wall instability. To this end, we have compared ruptured and unruptured IA domes from a human IA biobank.

Methods : Human aneurysms from the middle cerebral artery were obtained during microsurgery by resection of the IA dome after clipping of the neck, embedded in paraffin, and then sectioned and stained for the endothelial cell marker CD31 and the TJ proteins Claudin-5 and Zonula occludens-1 (ZO-1). The expression of these proteins was compared between ruptured and unruptured IAs. Results are expressed as a median (interquartile range).

Results : Histological analyses for CD31 revealed that endothelial cell coverage in ruptured (N=16) IAs tended to be decreased compared to unruptured (N=30) domes (27% (10-49) versus 38% (23-77) respectively, P=0.06). Interestingly, in ruptured aneurysms the expression of the TJ proteins Claudin-5 (1.70um (1.52-2.04)) and ZO-1 (2.29um (1.96-2.75) was lower in comparison with unruptured samples (Claudin-5: 2.15um (1.90-2.76), P<0.05; ZO-1: 2.66um (2.40-3.66), P<0.05).

Conclusion : Our study revealed reduced expression of Claudin-5 and ZO-1 in ruptured IAs in comparison with unruptured IA domes. Reduction in TJ proteins may lead to increased endothelial permeability thus favoring the accumulation of MRI contrast agent in the IA wall and the observation of VWE. Focusing on changes in endothelial characteristics and permeability may represent a new strategy to identify IAs at risk of rupture.