Mouse Model of Cerebral Aneurysm

Abstract

Background and Purpose-Rupture of cerebral aneurysm (CA) is the major cause of subarachnoid hemorrhage. Molecular mechanisms of this disease, however, remain unknown. To make possible genetic analysis of CA formation with genetically altered mice, we have successfully established a mouse model of saccular CA that recapitulates the essential features of human saccular CA. Methods-In C57black/6 male mice, various stages of CAs were experimentally induced at the right anterior cerebral artery-olfactory artery bifurcations by ligations of left common carotid arteries and posterior branches of bilateral renal arteries with high salt diet. Both light and electron microscopic studies were performed with the longitudinal sections of anterior cerebral artery-olfactory artery bifurcations. Results-In the treated group, various aneurysmal changes were detected in 14 of 18 mice. On the other hand, in the control group, no aneurysmal changes were found in 15 mice. In microscopic studies, aneurysmal changes were shown to include mainly fragmentation of internal elastic lamina, thinning of the smooth muscle cell layer, and degeneration of adventitial tissue, which were very similar to critical changes in human saccular CA. Conclusions-This mouse model of CA will be useful for studying the effects of complex determinants on CA formation and makes it possible to understand the pathogenesis of CA at the molecular level. Key Words: cerebral aneurysm Ⅲ genetics Ⅲ hemodynamics Ⅲ hypertension, renal Ⅲ mice S accular cerebral aneurysm (CA) consists mainly of thinning degenerated vascular walls in contrast to aortic aneurysm, which consists of thick walls containing advanced atherosclerotic changes. 1-3 Although recent reports have shown genetic analysis on aortic aneurysms formation, 4,5 the molecular mechanisms involved in the pathogenesis of saccular CA remain unclear. The major reasons might be that human specimens are often too deformed to examine and that there have not been any suitable animal models for genetic analysis. We have previously established experimentally induced CAs in rats and monkeys, 6 -8 which were characterized by specific initial changes such as fragmentation of internal elastic lamina and thinning of the medial smooth muscle cell layer. 9,10 Their pathological features appeared very similar to those of ruptured human CA 11 ; in fact, these are the only models that have been accepted for studying the pathogenesis of human CA. However, compared with rats and monkeys, a mouse model has great advantages in genetic analysis because of a variety of established gene-modulated mice. In this report, we demonstrate the first mouse model of saccular CA that uses genetically altered mice to explore the molecular mechanisms of CA formation and provide insights into new CA prevention and treatment strategies. Methods Experimentally Treated AnimalsAs described in our previous reports, 6 -8 20 male C57black/6CrSlc mice (SLC), which were 7 to 9 weeks of age, were subjected to ligations of the left common carotid arteries and ...

Complementary inhibition of cerebral aneurysm formation by eNOS and nNOS

“…At 7 weeks, CAs were induced as previously described. 12 Briefly, the left carotid artery was ligated under the general anesthesia by Fluothane. After 1 week, posterior branches of the bilateral renal artery were ligated.…”

“…In this study, we examined the role of eNOS in CA formation using experimental CA models of rats and mice. [11][12][13] …”

Association of intracranial aneurysms and meningiomas: a case-control study

“…To produce a constant cerebral perfusion pressure, arterial blood pressure should be increased by an amount equal to increases in intracranial pressure -caused by the tumor volume, even within the range of autoregulation. 1,3 Additionally, the chronic increase in arterial blood pressure may lead to an increase in hemodynamic stress, one of the principal factors of various degenerative changes in intracranial aneurysm formation, 6 on cerebral arteries around slowly growing meningiomas or in the entire brain, even though it would not cause definite systemic hypertension. This long-standing hemodynamic stress also leads to the formation of intracranial aneurysms in the contralateral hemisphere and the increased prevalence of other intracranial vascular diseases, such as isolated occlusion of intracranial arteries, in patients with meningiomas.…”

In Vivo Experimental Intracranial Aneurysm Models: A Systematic Review

“…One advantage of this model is the induction of cerebral aneurysms without direct manipulation of intracranial arteries. 2 These models could offer insight into the potential efficacy of pharmaceutical prevention of aneurysm formation and improved understanding of aneurysmal growth.…”