Two Diverse Hemodynamic Forces, a Mechanical Stretch and a High Wall Shear Stress, Determine Intracranial Aneurysm Formation

Intracranial aneurysm (IA) usually induced at a bifurcation site of intracranial arteries causes a lethal subarachnoid hemorrhage. Currently, IA is considered as a macrophage-mediated inflammatory disease triggered by a high wall shear stress (WSS) on endothelial cells. However, considered the fact that a high WSS can be observed at every bifurcation site, some other factors are required to develop IAs. We therefore aimed to clarify mechanisms underlying the initiation of IAs using a rat model. We found the transient outward bulging and excessive mechanical stretch at a prospective site of IA formation. Fibroblasts at the adventitia of IA walls were activated and produced (C-C motif) ligand 2 (CCL2) as well in endothelial cells loaded on high WSS at the earliest stage. Consistently, the mechanical stretch induced production of CCL2 in primary culture of fibroblasts and promoted migration of macrophages in a Transwell system. Our results suggest that distinct hemodynamic forces, mechanical stretch on fibroblasts and high WSS on endothelial cells, regulate macrophage-mediated IA formation.