Histological characterization and the role of biomechanical forces in intracranial aneurysm disease

Intracranial aneurysm (IA) is a disease characterized by an abnormal enlargement of the vessel lumen. It is a common pathology with a prevalence of 2-3% in the adult population. IAs are mostly small, quiescent and asymptomatic; yet upon rupture severe brain damage or even death is frequently encountered. Little is known about the etiology of IAs. Actually, their evolution is hard to predict and intricate medical decision. It is thus fundamental to better understand the physiopathology of IAs. It is generally assumed that the initiation, growth and rupture of IAs result from reciprocal action between the composition of the arterial wall and the hemodynamic forces to which it is exposed. In this thesis, I described the histopathological features of IAs prone to rupture. In addition, I investigated how wall shear stress induced by flowing blood and cyclic circumferential stretch incited by pulse waves influence the behavior of vascular endothelial cells

Role of hemodynamics in initiation/growth of intracranial aneurysms

Intracranial aneurysm (IA) is a disease of the vascular wall resulting in abnormal enlargement of the vessel lumen. It is a common pathology with a prevalence of 2%-3% in the adult population. IAs are mostly small, quiescent and asymptomatic; yet, upon rupture, severe brain damage or even death is frequently encountered. In addition to clinical factors, hemodynamic forces, mainly wall shear stress (WSS), have been associated with the initiation of IAs and possibly with their risk of rupture. However, the mechanism by which WSS contributes to aneurysm growth and rupture is not completely understood

Primary cilia control endothelial permeability by regulating expression and location of junction proteins

Aims: Wall shear stress (WSS) determines intracranial aneurysm (IA) development. Polycystic kidney disease (PKD) patients have a high IA incidence and risk of rupture. Dysfunction/absence of primary cilia in PKD endothelial cells (ECs) may impair mechano-transduction of WSS and favour vascular disorders. The molecular links between primary cilia dysfunction and IAs are unknown. Methods and results: Wild-type and primary cilia-deficient Tg737orpk/orpk arterial ECs were submitted to physiological (30 dynes/cm2) or aneurysmal (2 dynes/cm2) WSS and unbiased transcriptomics were performed. Tg737orpk/orpk ECs displayed a 5-fold increase in the number of WSS-responsive genes compared to wild-type cells. Moreover, we observed a lower trans-endothelial resistance and a higher endothelial permeability, which correlated with disorganized intercellular junctions in Tg737orpk/orpk cells. We identified ZO-1 as a central regulator of primary cilia-dependent endothelial junction integrity. Finally, clinical and histological characteristics of IAs from non-PKD and PKD patients were analysed. IAs in PKD patients were more frequently located in the middle cerebral artery (MCA) territory than in non-PKD patients. IA domes from the MCA of PKD patients appeared thinner with less collagen and reduced endothelial ZO-1 compared with IA domes from non-PKD patients. Conclusion: Primary cilia dampen the endothelial response to aneurysmal low WSS. In absence of primary cilia, ZO-1 expression levels are reduced, which disorganizes intercellular junctions resulting in increased endothelial permeability. This altered endothelial function may not only contribute to the severity of IA disease observed in PKD patients, but may also serve as a potential diagnostic tool to determine the vulnerability of IAs

Correlating Clinical Risk Factors and Histological Features in Ruptured and Unruptured Human Intracranial Aneurysms: The Swiss AneuX Study

Pathogenesis of intracranial aneurysm is complex and the precise biomechanical processes leading to their rupture are uncertain. The goal of our study was to characterize the aneurysmal wall histologically and to correlate histological characteristics with clinical and radiological factors used to estimate the risk of rupture. A new biobank of aneurysm domes resected at the Geneva University Hospitals (Switzerland) was used. Histological analysis revealed that unruptured aneurysms have a higher smooth muscle cell (SMC) content and a lower macrophage content than ruptured domes. These differences were associated with more collagen in unruptured samples, whereas the elastin content was not affected. Collagen content and type distribution were different between thick and thin walls of unruptured aneurysms. Classification of aneurysm domes based on histological characteristics showed that unruptured samples present organized wall rich in endothelial and SMCs compared with ruptured samples. Finally, aneurysm wall composition was altered in unruptured domes of patients presenting specific clinical factors used to predict rupture such as large dome diameter, dome irregularities, and smoking. Our study shows that the wall of aneurysm suspected to be at risk for rupture undergoes structural alterations relatively well associated with clinical and radiological factors currently used to predict this risk