Calcific nodule morphogenesis by heart valve interstitial cells is strain dependent.
Calcific nodule morphogenesis by heart valve interstitial cells is strain dependent.
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DOI：
10.1007/s10237-012-0377-8
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发表时间：
2013-01
影响因子：
3.5
通讯作者：
Merryman, W. David
中科院分区：
文献类型：
--
作者：
Fisher, Charles I.;Chen, Joseph;Merryman, W. David
关键词：
钙化性主动脉瓣病(CAVD)通过瓣膜不能完全打开和关闭而导致功能受损，但其发病原因尚不清楚。主动脉硬化与CAVD相关，并导致主动脉瓣暴露于更大的机械张力。转化生长因子β1(Transform Growth Functionβ1，TGF1)在病变瓣膜中含量丰富，已被证明与菌株结合可协同改变主动脉瓣间质细胞的表型。因此，我们研究了应变和转化生长因子-β-1在血管内皮细胞钙化中的作用。经转化生长因子-β-1处理后，应变诱导完整的单层聚集和钙化。通过创伤实验，我们证实转化生长因子-β1增加单层张力与α-平滑肌肌动蛋白(α-SMA)的表达平行。持续暴露于菌株会加速集合体钙化成成熟的结节，这些结节包含一个被凋亡环包围的坏死核。这一表型似乎是通过菌株在最初形成聚集体后对中航工业迁移的抑制来调节的。为了更好地解释外加应变对这一过程的物理影响程度，我们修改了经典的LAMé解，利用线弹性原理，揭示了应变放大是在支持结核形成的力学环境中发生的一个新特征。这些结果表明，应变可以影响结节形成的多个点：通过改变单层的张力，重塑细胞接触，迁移，细胞凋亡和矿化。因此，应变诱导的结瘤形成为制定应对CAVD的战略提供了新的方向。
Calcific aortic valve disease (CAVD) results in impaired function through the inability of valves to fully open and close, but the causes of this pathology are unknown. Stiffening of the aorta is associated with CAVD and results in exposing the aortic valves to greater mechanical strain. Transforming growth factor β1 (TGF-β1) is enriched in diseased valves and has been shown to combine with strain to synergistically alter aortic valve interstitial cell (AVIC) phenotypes. Therefore, we investigated the role of strain and TGF-β1 on the calcification of AVICs. Following TGF-β1 pretreatment, strain induced intact monolayers to aggregate and calcify. Using a wound assay, we confirmed that TGF-β1 increases tension in the monolayer in parallel with α-smooth muscle actin (αSMA) expression. Continual exposure to strain accelerates aggregates to calcify into mature nodules that contain a necrotic core surrounded by an apoptotic ring. This phenotype appears to be mediated by strain inhibition of AVIC migration after the initial formation of aggregates. To better interpret the extent to which externally applied strain physically impacts this process, we modified the classical Lamé solution, derived using principles from linear elasticity, to reveal strain magnification as a novel feature occurring in a mechanical environment that supports nodule formation. These results indicate that strain can impact multiple points of nodule formation: by modifying tension in the monolayer, remodeling cell contacts, migration, apoptosis, and mineralization. Therefore, strain induced nodule formation provides new directions for developing strategies to address CAVD.
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影响因子：
24
作者：
Goldbarg, Seth H.;Elmariah, Sammy;Fuster, Valentin
通讯作者：
Fuster, Valentin
影响因子：
3.5
作者：
Haskett, Darren;Johnson, Gregory;Vande Geest, Jonathan
通讯作者：
Vande Geest, Jonathan
影响因子：
--
作者：
Merryman, W. David;Liao, Jun;Sacks, Michael S.
通讯作者：
Sacks, Michael S.
影响因子：
6.9
作者：
Cushing, MC;Liao, JT;Anseth, KS
通讯作者：
Anseth, KS
影响因子：
4.6
作者：
Jian, B;Narula, N;Levy, RJ
通讯作者：
Levy, RJ