Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-l
Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-l
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DOI：
10.1073/pnas.96.7.3819
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发表时间：
1999-03-30
影响因子：
11.1
通讯作者：
Ramirez, F
中科院分区：
文献类型：
--
作者：
Pereira, L;Lee, SY;Ramirez, F
主动脉夹层动脉瘤是马凡综合征 (MFS) 的标志，也是原纤维蛋白 1 突变的结果，纤维蛋白 1 是弹性蛋白相关的细胞外微原纤维的主要成分。目前尚不清楚 fibrillin-1 的功能障碍是否会通过破坏微原纤维组装、损害已建立的弹性纤维的稳态或通过这两种机制的组合来扰乱弹性血管壁维持血流动力学应力的能力。导致主动脉壁弹性板层机械塌陷的致病序列也是未知的。小鼠 fibrillin-1 基因的靶向突变最近表明，fibrillin-1 的缺乏会降低组织稳态，而不是弹性纤维的形成。在这里，我们描述了另一种基因靶向突变 mgR，它表明 fibrillin-1 的表达不足同样会导致类似 MFS 的表现，mgR/mgR 标本的组织病理学分析表明夹层动脉瘤自然史中存在中层钙化、炎症纤维增殖反应和炎症介导的弹性组织溶解。更一般地说，与正常和突变 fibrillin-1 等位基因的各种组合相关的表型严重程度表明，基于微原纤维的水平和完整性的血管壁功能性崩溃的阈值现象。
Dissecting aortic aneurysm is the hallmark of Marfan syndrome (MFS) and the result of mutations in fibrillin-1, the major constituent of elastin-associated extracellular microfibrils. It is yet to be established whether dysfunction of fibrillin-1 perturbs the ability of the elastic vessel wall to sustain hemodynamic stress by disrupting microfibrillar assembly, by impairing the homeostasis of established elastic fibers, or by a combination of both mechanisms, The pathogenic sequence responsible for the mechanical collapse of the elastic lamellae in the aortic wall is also unknown. Targeted mutation of the mouse fibrillin-1 gene has recently suggested that deficiency of fibrillin-1 reduces tissue homeostasis rather than elastic fiber formation. Here we describe another gene-targeting mutation, mgR, which shows that underexpression of fibrillin-1 similarly leads to MFS-like manifestations, Histopathological analysis of mgR/mgR specimens implicates medial calcification, the inflammatory-fibroproliferative response, and inflammation-mediated elastolysis in the natural history of dissecting aneurysm. More generally, the phenotypic severity associated with various combinations of normal and mutant fibrillin-1 alleles suggests a threshold phenomenon for the functional collapse of the vessel wall that is based on the level and the integrity of microfibrils.