Published Online
on November 22, 2006

A more recent version of this article appeared on January 1, 2007

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Submitted on May 23, 2006
Revised on August 9, 2006
Accepted on August 30, 2006

Macrophage-Derived Matrix Metalloproteinase-2 and -9 Promote the Progression of Cerebral Aneurysms in Rats

Tomohiro Aoki MD; Hiroharu Kataoka MD, PhD^*; Masafumi Morimoto MD, PhD; Kazuhiko Nozaki MD, PhD; and Nobuo Hashimoto MD, PhD

From the Kyoto University, Graduate School of Medicine, Japan.

^* To whom correspondence should be addressed. E-mail: kataoka{at}kuhp.kyoto-u.ac.jp.

Background and Purpose--Mechanisms of initiation, progression and rupture of cerebral aneurysms have not yet been fully understood despite its clinical significance. Matrix metalloproteinases (MMPs) are a family of proteinases which are involved in the remodeling of vascular walls. In the present study, we investigated the significance of MMPs in the progression of cerebral aneurysms.

Methods--Cerebral aneurysms were experimentally induced in 7-week-old male Sprague-Dawley rats. MMP-2 and MMP-9 expression was examined by immunohistochemistry and RT-PCR. Gelatinase activity in aneurysmal walls was assessed by in situ zymography. A selective inhibitor for MMP-2, -9 and -12, tolylsam, was used to examine the effect of inhibition of MMP-2 and MMP-9.

Results--Macrophages infiltrated in arterial walls of experimentally induced rat cerebral aneurysms and expressed MMP-2 and -9. Macrophage infiltration and MMP expression was increased with the progression of aneurysms. Gelatinase activity attributable to MMP-2 and MMP-9 increased in arterial walls of rat cerebral aneurysms. Furthermore, tolylsam reduced the ratio of advanced aneurysms in our rat model.

Conclusions--These data suggest that macrophage-derived MMP-2 and -9 may play an important role in the progression of cerebral aneurysms. The findings of this study will shed a new light into the pathogenesis of cerebral aneurysms and highlight the importance of inflammatory response causing the degeneration of extracellular matrix in the process of this disease.

Key words: aneurysm • inflammation • macrophages • matrix metalloproteinases

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