Lack of primary cilia primes shear-induced endothelial-to-mesenchymal transition.
Lack of primary cilia primes shear-induced endothelial-to-mesenchymal transition.
复制标题
DOI：
10.1161/circresaha.110.231860
复制
发表时间：
2011-04-29
影响因子：
20.1
通讯作者：
Hierck BP
中科院分区：
文献类型：
--
作者：
Egorova AD;Khedoe PP;Goumans MJ;Yoder BK;Nauli SM;ten Dijke P;Poelmann RE;Hierck BP
初级纤毛是细胞突起，用作流体流动的机械传感器。在内皮细胞 (EC) 中，它们的作用是将局部血流信息转化为功能反应，例如一氧化氮的产生和基因表达的启动。纤毛存在于 EC 上低流量或扰动区域，而在高流量区域不存在。在胚胎心脏中，高流量状态适用于心内膜垫区域，并且此处纤毛的缺失与内皮-间质转化（EndoMT）的过程一致。在这项研究中，我们研究了初级纤毛在定义 EC 对流体剪切应力的响应和 EndoMT 中的作用。使用 Tg737/Ift88 突变的无纤毛小鼠胚胎 EC 来比较对流体剪切应力的响应与有纤毛 EC 的响应。在体外，非纤毛 EC 经历剪切诱导的 EndoMT，并伴随着 Klf4 的下调。这种 Tgfβ/Alk5 依赖性转化可以通过阻断 Tgfβ 信号传导、Klf4 过度表达或拯救初级纤毛来预防。在 Tg737orpk/orpk 胚胎的心脏中，Tgfβ/Alk5 信号在 EC 通常有纤毛的区域被激活，但现在由于突变而缺乏纤毛。在这些区域中，EC 显示 Smad2 磷酸化和 αSMA 表达增加。这项研究证明初级纤毛在使 EC 易于剪切诱导的 Tgfβ/Alk5 信号传导和 EndoMT 激活中发挥核心作用，从而提供初级纤毛和流动相关内皮性能之间的功能联系。
Primary cilia are cellular protrusions which serve as mechanosensors for fluid flow. In endothelial cells (EC) they function in transducing local blood flow information into functional responses, like nitric oxide production and initiation of gene expression. Cilia are present on EC in areas of low or disturbed flow and absent in areas of high flow. In the embryonic heart high flow regime applies to the endocardial cushion area, and the absence of cilia here coincides with the process of endothelial-to-mesenchymal transition (EndoMT). In this study we investigate the role of the primary cilium in defining the responses of EC to fluid shear stress and in EndoMT. Non-ciliated mouse embryonic EC with a mutation in Tg737/Ift88 were used to compare the response to fluid shear stress to that of ciliated EC. In vitro, non-ciliated EC undergo shear-induced EndoMT which is accompanied by downregulation of Klf4. This Tgfβ/Alk5 dependent transformation is prevented by blocking Tgfβ signaling, overexpression of Klf4, or rescue of the primary cilium. In the hearts of Tg737orpk/orpk embryos Tgfβ/Alk5 signaling was activated in areas in which EC would normally be ciliated, but now lack cilia due to the mutation. In these areas EC show increased Smad2 phosphorylation and expression of αSMA. This study demonstrates the central role of primary cilia in rendering EC prone to shear-induced activation of Tgfβ/Alk5 signaling and EndoMT, and thereby provides a functional link between primary cilia and flow related endothelial performance.