Molecular events regulating the pathogenesis of intracranial aneurysms: Special insight on hemodynamics and chronic inflammation

Intracranial aneurysm (IA) can cause a lethal subarachnoid hemorrhage after rupture. Thereby, the correct understanding of the pathogenesis of the disease is essential to develop a novel therapeutic strategy to prevent progression. The accumulating evidence from simulation of hemodynamics targeting human cases has implied the role of hemodynamic force in IAs. In another point of view, experimental evidence mainly from animal studies has clarified the crucial role of macrophage-mediated long lasting-inflammation in the pathogenesis. However, how hemody namic stress triggers such molecular events in arterial walls to develop IAs remains unclear. Recent experimental studies have revealed some of the potential machineries regulating hemodynamic stress-triggered IA formation. High walls shear stress activates endothelial cells and induces expression of MCP-1 at the earliest stage of IA formation. At adventitia, mechanical stretch induces MCP-1 expression in fibroblasts as well. MCP-1-mediated infiltration of macrophages into intracranial arterial walls thus occurs. In infiltrating macrophages, EP2 functions to exacerbate inflammation through formation of positive feedback loop, synergistic action with TNF-α and auto-amplification loop among macrophages. Given the nature of IAs as a vascular disease, further studies focused on hemodynamic force-mediated molecular events regulating the pathogenesis are necessary to understand the whole picture of the disease.