Pathogenesis of cerebral aneurysms: evidence using experimentally induced cerebral aneurysm models

ABSTRACT

Background: Cerebral saccular aneurysm is a major cause of subarachnoid hemorrhage, one of the cerebrovascular diseases with the highest mortality. The mechanisms underlying the development of aneurysm, however, still remain unclear. Objective: The authors have made a series of reports on an animal model of experimentally induced cerebral aneurysms that resemble human cerebral aneurysms in their location and morphology. The objective of this brief review is to introduce our evidence about the pathogenesis of cerebral aneurysms using the experimentally induced cerebral aneurysm model, particularly focused upon the role of nitric oxide (NO) and shear stress on degenerative changes of the arterial wall during aneurysm development. Methods: We first introduce methods of aneurysm-inducing surgery, and then refer to morphological analysis of aneurysmal induction. Next, we explain the association between aneurysmal development and shear stress and NO. Finally, we show several mechanisms of aneurysmal development using genetically modified animals. Results and conclusion: In our animal model, cerebral aneurysms are induced in rats, monkeys, and mice by ligation of the unilateral common carotid artery and renal hypertension, suggesting that an increase in hemodynamic stress is a key requirement for the aneurysm development. Our morphological and molecular studies suggest that increased wall shear stress, iNOS-derived NO, MMP-2 \& 9, cathepsin B, NF-κB, interleukin-1β, and endothelin B receptor are associated with the progression of cerebral aneurysms. Statin and Nifedipine may be possible drugs for the prevention of cerebral aneurysm development.