Phenotypic alteration of vascular smooth muscle cells precedes elastolysis in a mouse model of Marfan syndrome
Phenotypic alteration of vascular smooth muscle cells precedes elastolysis in a mouse model of Marfan syndrome
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DOI：
10.1161/01.res.88.1.37
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发表时间：
2001-01-05
影响因子：
20.1
通讯作者：
Dietz, HC
中科院分区：
文献类型：
--
作者：
Bunton, TE;Biery, NJ;Dietz, HC
马凡氏综合征与主动脉瘤引起的早期死亡有关。这种情况是由编码细胞外微纤维的主要成分--β-内酰胺酶-1的基因（FBN 1）突变引起的。先前的观察表明，在胎儿发育后期，微纤丝的缺乏导致弹性纤维组装失败。Fbn 1的靶向亚型等位基因（mgR）纯合子小鼠显示血管壁异常的可预测序列，包括弹性纤维钙化、基质元素过度沉积、弹性蛋白溶解和内膜增生。在这里，我们描述了以前未被认识到的一致性发现弹性血管从马方综合征患者。此外，mgR小鼠的超微结构分析揭示了引发破坏性变化的细胞事件。第一个可检测到的异常是弹性膜异常光滑的表面，表现出通常由Escherin-1介导的细胞附着的丧失。相邻细胞的表达谱发生改变，伴随着形态学变化，但保留血管平滑肌细胞标志物的表达。在早期血管病变中，这些形态异常的平滑肌细胞的异常合成库包括弹性蛋白，以及其他基质元素和基质金属蛋白酶9，一种已知的弹性蛋白溶解介质。最终，细胞突起与弹性纤维变细和破碎的区域相关。这些数据表明，细胞附着的丧失是合成和重塑弹性基质的非生产性程序的信号。对马凡氏综合征血管疾病发病机制的深入了解将有助于制定治疗策略。
Marfan syndrome is associated with early death due to aortic aneurysm. The condition is caused by mutations in the gene (FBN1) encoding fibrillin-1, a major constituent of extracellular microfibrils. Prior observations suggested that a deficiency of microfibrils causes failure of elastic fiber assembly during late fetal development. Mice homozygous for a targeted hypomorphic allele (mgR) of Fbn1 revealed a predictable sequence of abnormalities in the vessel wall including elastic fiber calcification, excessive deposition of matrix elements, elastolysis, and intimal hyperplasia. Here we describe previously unrecognized concordant findings in elastic vessels from patients with Marfan syndrome. Furthermore, ultrastructural analysis of mgR mice revealed cellular events that initiate destructive changes. The first detectable abnormality was an unusually smooth surface of elastic laminae, manifesting the loss of cell attachments that are normally mediated by fibrillin-1, Adjacent cells adopted alteration in their expression profile accompanied by morphological changes but retained expression of vascular smooth muscle cell markers. The abnormal synthetic repertoire of these morphologically abnormal smooth muscle cells in early vascular lesions included elastin, among other matrix elements, and matrix metalloproteinase 9, a known mediator of elastolysis. Ultimately, cell processes associated with zones of elastic fiber thinning and fragmentation. These data suggest that the loss of cell attachments signals a nonproductive program to synthesize and remodel an elastic matrix. This refined understanding of the pathogenesis of vascular disease in Marfan syndrome will facilitate the development of therapeutic strategies.