Chronic inflammation in intracranial aneurysm formation

Intracranial aneurysm (IA) is a cerebrovascular disease usually affected the bifurcation sites of intracranial arteries. IA is socially important because IA can develop a lethal subarachnoid hemorrhage after rupture. However, today, there is no medical treatment for IAs because of the lack of knowledge regarding the mechanisms regulating IA formation. Experimental analyses using human IA specimen have revealed the presence of long-lasting inflammation in IA lesions. In other point of view, from studies of flow dynamics, IA formation is presumed to be triggered under high wall shear stress loaded on arterial bifurcations. Nonetheless, the mechanisms regarding how IA formation is regulated under high wall shear stress and how the inflammation lasts for a long period remain to be elucidated. Recently, experimental studies using rodent IA models have revealed a critical role of prostaglandin (PG) E2 signaling to IA formation. In brief, COX-2, a PGE2-producing enzyme, is induced under high wall shear stress in endothelial cells. COX-2-producing PGE2, then, activates NF-κB, a critical transcription factor for IA formation, via EP2. Because NF-κB transcriptionally induces COX-2, a positive feedback loop consisting of COX-2-PGE2-EP2-NF-κB signaling is formed and high wall shear stress induced inflammation becomes chronic. Here, as a result of NF-κB-mediated MCP-1 induction, macrophages infiltrate in IA walls and expand inflammation into whole arterial walls beyond endothelial cells via secreting a large amount of pro-inflammatory molecules. In summary, the presence of positive feedback loop and macrophage infiltration are two key events regulating the chronicity of inflammation contributing to IA formation.