Inhibition of Diaphanous Formin Signaling In Vivo Impairs Cardiovascular Development and Alters Smooth Muscle Cell Phenotype.
Inhibition of Diaphanous Formin Signaling In Vivo Impairs Cardiovascular Development and Alters Smooth Muscle Cell Phenotype.
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DOI：
10.1161/atvbaha.115.305879
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发表时间：
2015-11
期刊：
影响因子：
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通讯作者：
Mack CP
中科院分区：
文献类型：
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作者：
Weise-Cross L;Taylor JM;Mack CP
我们和其他人以前已经表明，RhoA依赖性刺激心肌蛋白相关转录因子（MRTF）核定位促进平滑肌细胞（SMC）标记基因的表达。本研究的目的是提供直接的体内证据表明，肌动蛋白聚合的透明相关formin有助于SMC分化和/或表型的调节。有条件的cre为基础的遗传方法被用来过表达一个充分表征的显性负变异mDia 1（DNmDia）在SMC。在SM 22表达细胞中的DNmDia表达导致约20%的小鼠的胚胎和围产期死亡，这是由于心肌发育和外周血管SMC投资的缺陷。虽然大多数DNmDia+/SM 22 Cre+小鼠没有表现出明显的表型，但颈动脉结扎后发生的SMC分化标志物基因表达的再表达被延迟，并且这种效应伴随着MRTF-A核定位的显著降低。有趣的是，新生内膜生长受到SMC中DNmDia表达的抑制，这可能是由于SMC定向迁移的缺陷，而不是SMC增殖或存活的缺陷。最后，通过使用他莫昔芬诱导的SM MHCCreERT 2系，我们表明SMC特异性诱导成年小鼠中的DNmDia降低SMC标记基因表达。我们的证明，透明相关的MRTF信号在心脏和血管发育中起作用，SMC表型的维持提供了重要的新证据，Rho/肌动蛋白/MRTF信号在心血管功能中起着至关重要的作用。
We and others have previously shown that RhoA-dependent stimulation of myocardin related transcription factor (MRTF) nuclear localization promotes smooth muscle cell (SMC) marker gene expression. The goal of the present study was to provide direct in vivo evidence that actin polymerization by the diaphanous-related formins contributes to the regulation of SMC differentiation and/or phenotype. Conditional cre-based genetic approaches were used to over-express a well-characterized dominant negative variant of mDia1 (DNmDia) in SMC. DNmDia expression in SM22 expressing cells resulted in embryonic and perinatal lethality in ~20% of mice due to defects in myocardial development and SMC investment of peripheral vessels. While most DNmDia+/SM22Cre+ mice exhibited no overt phenotype, the re-expression of SMC differentiation marker gene expression that occurs following carotid artery ligation was delayed, and this effect was accompanied by a significant decrease in MRTF-A nuclear localization. Interestingly, neointima growth was inhibited by expression of DNmDia in SMC and this was likely due to a defect in directional SMC migration and not to defects in SMC proliferation or survival. Finally, by using the tamoxifen-inducible SM MHCCreERT2 line, we showed that SMC-specific induction of DNmDia in adult mice decreased SMC marker gene expression. Our demonstration that diaphanous-related formin signaling plays a role in heart and vascular development and the maintenance of SMC phenotype provides important new evidence that Rho/actin/MRTF signaling plays a critical role in cardiovascular function.