Hypoxic microenvironment as a crucial factor triggering events leading to rupture of intracranial aneurysm

Abstract Background: Subarachnoid hemorrhage being the rupture of intracranial aneurysm (IA) as a major cause has a high mortality rate in spite of technical advancement in treatment interventions. Thereby, it is mandatory for social health to clarify mechanisms regulating rupture of IAs and to develop a novel therapeutic strategy to prevent rupture. Following the recent experimental studies, we and others have clarified the formation of vasa vasorum in IA lesions presumably for inflammatory cells to infiltrate in lesions as the potential histopathological alternation leading to rupture. Main Body: We first clarified the origin of vasa vasorum as arteries located at the brain surface in 3D-immunohistochemistry with tissue transparency. We then found the presence of hypoxic microenvironment mainly at the adventitia of intracranial arteries where IA is induced by using the Pimonidazole-based probe in vivo. Among angiogenic factors potentially responsible for the formation of vasa vasorum, the production of vascular endothelial growth factor (VEGF) from cultured macrophages in such a hypoxic condition was identified in vitro and in vivo experiment using rupture-prone IA lesions induced in a rat model reproduced the production of VEGF from infiltrating macrophages. We further examined VEGF production in human unruptured IA lesions and found the accumulation of VEGF in the lesions, supporting the production of VEGF in situ. Finally, the VEGF-dependent induction of neovessels from arteries on brain surface was confirmed in experiments placing the sheet for the slow-release of VEGF on brain surface. Here, because intracranial arteries histologically lack vasa vasorum and are surrounded by cerebrospinal fluid space, the formation of the hypoxic microenvironment could be a character of intracranial arteries and inflammatory responses there could further facilitate such a condition to induce vasa vasorum. In addition, the enlargement of the lesions and the disruption of physical barrier like arachnoid might be a necessary factor for the migration of vasa vasorum into subarachnoid space from arteries on brain surface.Conclusions: The findings from the present study have revealed the potential role of hypoxic microenvironment and hypoxia-induced VEGF production as a machinery triggering rupture of IAs via providing root for inflammatory cells in lesions to exacerbate inflammation.