The molecular mechanisms of initiation, progression, rupture of cerebral aneurysms and development of a preventive treatment for it

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We induced experimentally cerebral aneurysms in rats and mice.Immunohistochemistry and RT-PCR showed the upregulated expression of IL-1β mainly in medial smooth muscle cells. In IL-1β deficient mice, the ratio of advanced aneurysms was significantly reduced and the number of apoptotic cells in aneurysmal walls decreased. These data suggested that IL-1β promoted the progression of cerebral aneurysms by inducing apoptosis in smooth muscle cells.Immunohistochemistry and RT-PCR showed the expression of MMP-2 and MMP-9 increased in aneurysmal walls with aneurysm progression. In the early stage of aneurysm formation, macrophages accumulated into aneurysmal walls and secreted MMP-2 and-9. The treatment with a selective inhibitor of MMP-2 and-9, Tolylsam, significantly decreased the ratio of advanced aneurysms. These data indicated that MMP-2 and-9 secreted by macrophages promoted the progression of aneurysms.In RT-PCR, the expression of endogenous inhibitor of MMPs, TIMP-1 and-2, increased in the early stage of aneurysm formation but not in the late stage, making the ratio of MMP/TIMP elevated in advanced aneurysms. In Both TIMP-1 and TIMP-2 deficiency mice, the progression of cerebral aneurysms was promoted, demonstrating the suppressive role of TIMP-1 and-2 in aneurysm progression.In a linkage analysis of 24 families with cerebral aneurysms, TNF receptor superfamily 13B was proved to be a susceptible gene of human cerebral aneurysm.