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

Subarachnoid hemorrhage being the rupture of intracranial aneurysm (IA) as a major cause has quite poor prognosis, despite the modern technical advances. Thereby, the mechanisms underlying the rupture of lesions should be clarified. Recently, 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. In the present study, we clarified the origin of vasa vasorum as arteries located at the brain surface using 3D-immunohistochemistry with tissue transparency. Using Hypoxyprobe, we then found the presence of hypoxic microenvironment mainly at the adventitia of intracranial arteries where IA is formed. In addition, the production of vascular endothelial growth factor (VEGF) from cultured macrophages in such a hypoxic condition was identified. Furthermore, we found the accumulation of VEGF both in rupture-prone IA lesions induced in a rat model and human unruptured IA lesions. Finally, the VEGF-dependent induction of neovessels from arteries on brain surface was confirmed. 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.