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

我们实验性地诱导了大鼠和小鼠的脑动脉瘤。免疫组织化学和RT-PCR显示IL-1β主要在内侧平滑肌细胞表达上调。IL-1β缺失小鼠晚期动脉瘤比例明显降低，瘤壁凋亡细胞数量明显减少。这些数据表明IL-1β通过诱导平滑肌细胞凋亡促进脑动脉瘤的进展。免疫组织化学和RT-PCR显示，随着动脉瘤的进展，瘤壁中MMP-2和MMP-9的表达增加。在动脉瘤形成早期，巨噬细胞聚集在动脉瘤壁上，分泌MMP-2和9。使用选择性MMP-2和9抑制剂tolysam治疗可显著降低晚期动脉瘤的比例。这些数据表明巨噬细胞分泌的MMP-2和mmp -9促进了动脉瘤的进展。在RT-PCR中，内源性MMPs抑制剂TIMP-1和TIMP- 2的表达在动脉瘤形成早期升高，而在晚期没有升高，使得MMP/TIMP比值在晚期动脉瘤中升高。在TIMP-1和TIMP-2缺失小鼠中，脑动脉瘤的进展均得到促进，表明TIMP-1和2在动脉瘤进展中的抑制作用。在对24个脑动脉瘤家族的连锁分析中，TNF受体超家族13B被证实是人类脑动脉瘤的易感基因。

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.