Objective

Mouse models of Marfan syndrome (MFS) with Fibrillin 1 (Fbn1) variant C1041G exhibit cardiovascular abnormalities, including myxomatous valve disease (MVD) and aortic aneurism, with structural extracellular matrix (ECM) dysregulation. In this study, we examine the structure-function-mechanics relations of the mitral valve related to specific transitions in ECM composition and organization in progressive MVD in MFS mice from Postnatal day (P)7 to 1 year-of-age.

Approach and results

Mechanistic links between mechanical forces and biological changes in MVD progression were examined in Fbn1^C1041G/+ MFS mice. By echocardiography, mitral valve dysfunction is prevalent at 2 months with a decrease in cardiac function at 6 months, followed by a preserved cardiac function at 12 months. Mitral valve (MV) regurgitation occurs in a subset of mice at 2–6 months, while progressive dilatation of the aorta occurs from 2 to 12 months. Mitral valve tissue mechanical assessments using a uniaxial Permeabilizable Fiber System demonstrate decreased stiffness of MFS MVs at all stages. Histological and microscopic analysis of ECM content, structure, and fiber orientation demonstrate that alterations in ECM mechanics, composition, and organization precede functional abnormalities in Fbn1^C1041G/+MFS MVs. At 2 months, ECM abnormalities are detected with an increase in proteoglycans and decreased stiffness of the mitral valve. By 6–12 months, collagen fiber remodeling is increased with abnormal fiber organization in MFS mitral valve leaflets. At the same time, matrifibrocyte gene expression characteristic of collagen-rich connective tissue is increased, as detected by RNA in situ hybridization and qPCR. Together, these studies demonstrate early prevalence of proteoglycans at 2 months followed by upregulation of collagen structure and organization with age in MVs of MFS mice.

Conclusions

Altogether, our data indicate dynamic regulation of mitral valve structure, tissue mechanics, and function that reflect changes in ECM composition, organization, and gene expression in progressive MVD. Notably, increased collagen fiber organization and orientation, potentially dependent on increased matrifibrocyte cell activity, is apparent with altered mitral valve mechanics and function in aging MFS mice.

中文翻译：

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马凡综合征小鼠模型二尖瓣细胞外基质、组织力学和功能的动态变化

客观的

具有原纤维蛋白1 (Fbn1)变体 C1041G的马凡综合征 (MFS) 小鼠模型表现出心血管异常，包括粘液瘤性瓣膜病 (MVD) 和主动脉瘤，以及结构性细胞外基质 (ECM) 失调。在这项研究中，我们检查了 MFS 小鼠从出生后第 7 天到 1 岁的进行性 MVD 中与 ECM 组成和组织的特定转变相关的二尖瓣的结构-功能-力学关系。

方法和结果

在Fbn1 ^C1041G/+ MFS 小鼠中检查了机械力与 MVD 进展的生物变化之间的机械联系 。通过超声心动图检查，二尖瓣功能障碍在 2 个月时普遍存在，6 个月时心功能下降，随后 12 个月时心功能保留。部分小鼠在 2-6 个月时出现二尖瓣 (MV) 反流，而主动脉进行性扩张则在 2 至 12 个月时出现。使用单轴渗透性纤维系统进行的二尖瓣组织机械评估表明，MFS MV 在所有阶段的硬度均有所下降。ECM 内容、结构和纤维取向的组织学和显微镜分析表明，ECM 力学、组成和组织的改变先于Fbn1 ^C1041G/+ MFS MV 的功能异常。2 个月时，检测到 ECM 异常，蛋白聚糖增加，二尖瓣硬度降低。6-12 个月时，胶原纤维重塑增加，MFS 二尖瓣小叶纤维组织异常。同时，通过 RNA原位杂交和 qPCR 检测到，富含胶原蛋白的结缔组织特征的基质纤维细胞基因表达增加。总之，这些研究表明，MFS 小鼠 MV 中蛋白多糖在 2 个月时就出现了早期流行，随后胶原蛋白结构和组织随着年龄的增长而上调。

结论

总而言之，我们的数据表明二尖瓣结构、组织力学和功能的动态调节反映了进行性 MVD 中 ECM 组成、组织和基因表达的变化。值得注意的是，胶原纤维组织和方向的增加，可能依赖于基质纤维细胞活性的增加，在衰老的 MFS 小鼠中，二尖瓣力学和功能的改变是显而易见的。