Abstract TP79: Imbalance Between Activation Of Matrix Metalloprotease And Its Inhibition May Facilitate The Growth Of Cerebral Aneurysm In Female Rats

Abstract

Introduction: Cerebral aneurysms are a major cause of subarachnoid hemorrhage . Despite the catastrophic consequences of their rupture, not all mechanisms underlying the formation, progression, and rupture of cerebral aneurysms are fully understood. Using our model of reproducible cerebral aneurysms in oophorectomized rats we have documented the pathogenesis of cerebral aneurysms. Methionine-induced hyperhomocysteinemia which participates in coronary disease or stroke, is also associated with cerebral aneurysm formation. Whether it facilitates the growth and rupture of cerebral aneurysms remains obscure. We explored the role of methionine in the growth and rupture of cerebral aneurysms. Methods: We subject 13 week-old female Sprague-Dawley rats fed an 8% high-salt diet to bilateral oophorectomy and ligation of the right common carotid artery. Four weeks later they underwent ligation of the bilateral posterior renal artery divided into 2 groups; one group did and the other did not receive 1g/kg/day methionine in the drinking water. The aneurysmal rupture rate and morphologic- and genomic changes in the 2 groups were compared at 12 weeks. Results: The incidence of cerebral aneurysm formation was the same in both groups. While the rate of rupture was not higher in the methionine group, their aneurysms were larger and oxidative stress-related NOX4, Rac1, and apoptosis-related Rac1 were up-regulated. Interestingly, the expression of MMP-9 was increased as was the ratio of MMP-9 to TIMP2 but not of MMP-9 to TIMP1, suggesting vascular degradation due to an imbalance between the activation and inhibition of extracellular matrix metalloprotease. Conclusion: Our findings suggest that excessive vascular degradation due to oxidative stress and apoptosis induced by methionine contribute to the progression of cerebral aneurysms in oophorectomized rats.