Impaired vascular smooth muscle cell force-generating capacity and phenotypic deregulation in Marfan Syndrome mice
Impaired vascular smooth muscle cell force-generating capacity and phenotypic deregulation in Marfan Syndrome mice
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DOI：
10.1016/j.bbadis.2019.165587
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发表时间：
2020-01-01
影响因子：
6.2
通讯作者：
Martins Laurindo, Francisco Rafael
中科院分区：
文献类型：
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作者：
Nolasco, Patricia;Fernandes, Carolina Goncalves;Martins Laurindo, Francisco Rafael
fibrillin-1 突变决定马凡综合征 (MFS) 中胸主动脉瘤/夹层 (TAAD) 的机制尚不清楚。大多数主动脉瘤是由机械信号失调演变而来，逐渐演变成血管平滑肌细胞（VSMC）产生力的能力受损，并伴有合成表型转换。然而，人们对 MFS 病理生理学中 VSMC 机械反应知之甚少。在这里，我们研究了从 3 个月大的 mg Delta(lpn) MFS 小鼠中培养的主动脉 VSMC 的牵引力产生能力，以及形态功能和蛋白质组数据。与野生型 (WT) VSMC 相比，培养的 MFS-VSMC 表现出明显的表型变化，细胞增殖标记物过度表达，但分化标记物表达较低 (calponin-1) 或较高 (SM α肌动蛋白和 SM22)。与此同时，增加的细胞面积及其复杂的非梭形形状表明可能向间充质样表型转变，这通过多个标记物（例如 N-钙粘蛋白、Slug）得到证实。 MFS-VSMC 的蛋白质组谱与 WT-VSMC 的蛋白质组谱不同，特别是肌动蛋白细胞骨架调节蛋白的表达较低。因此，MFS-VSMC 在生理基底刚度下表现出较低的牵引力产生能力和受损的收缩力矩，并且显着减弱了对增强的基底刚度的牵引力响应。与 WT-VSMC 相比，这种机械反应受损与粘着斑数量减少、形态改变和离域以及肌动蛋白应力纤维网络紊乱相关。在6月龄小鼠培养的VSMC中，表型变化减弱，WT-VSMC和MFS-VSMC产生的牵引力较小，可能与VSMC老化有关，但没有明显的衰老。总之，MFS-VSMC 显示出受损的力生成能力，伴随着与受损的细胞骨架/粘着斑组织相关的间充质样表型转换。因此，MFS 相关的 TAAD 涉及其他 TAAD 类型常见的机械反应损伤，但机制不同。
Mechanisms whereby fibrillin-1 mutations determine thoracic aorta aneurysms/dissections (TAAD) in Marfan Syndrome (MFS) are unclear. Most aortic aneurysms evolve from mechanosignaling deregulation, converging to impaired vascular smooth muscle cell (VSMC) force-generating capacity accompanied by synthetic phenotype switch. However, little is known on VSMC mechanoresponses in MFS pathophysiology. Here, we investigated traction force-generating capacity in aortic VSMC cultured from 3-month old mg Delta(lpn) MFS mice, together with morpho-functional and proteomic data. Cultured MFS-VSMC depicted marked phenotype changes vs. wild-type (WT) VSMC, with overexpressed cell proliferation markers but either lower (calponin-1) or higher (SM alphaactin and SM22) differentiation marker expression. In parallel, the increased cell area and its complex non-fusiform shape suggested possible transition towards a mesenchymal-like phenotype, confirmed through several markers (e.g. N-cadherin, Slug). MFS-VSMC proteomic profile diverged from that of WT-VSMC particularly regarding lower expression of actin cytoskeleton-regulatory proteins. Accordingly, MFS-VSMC displayed lower traction force-generating capacity and impaired contractile moment at physiological substrate stiffness, and markedly attenuated traction force responses to enhanced substrate rigidity. Such impaired mechanoresponses correlated with decreased number, altered morphology and delocalization of focal adhesions, as well as dis-organized actin stress fiber network vs. WT-VSMC. In VSMC cultured from 6-month-old mice, phenotype changes were attenuated and both WT-VSMC and MFS-VSMC generated less traction force, presumably involving VSMC aging, but without evident senescence. In summary, MFS-VSMC display impaired force-generating capacity accompanying a mesenchymal-like phenotype switch connected to impaired cytoskeleton/focal adhesion organization. Thus, MFS-associated TAAD involves mechanoresponse impairment common to other TAAD types, but through distinct mechanisms.