Oscillatory Flow Modulates Mechanosensitive klf2a Expression through trpv4 and trpp2 during Heart Valve Development
Oscillatory Flow Modulates Mechanosensitive klf2a Expression through trpv4 and trpp2 during Heart Valve Development
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DOI：
10.1016/j.cub.2015.03.038
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发表时间：
2015-05-18
期刊：
影响因子：
9.2
通讯作者：
Vermot, Julien
中科院分区：
文献类型：
--
作者：
Heckel, Emilie;Boselli, Francesco;Vermot, Julien
在脊椎动物中，心脏形态发生需要心脏泵血，改变心肌收缩力会导致异常心内流动力和瓣膜缺陷[1-3]。在发育中的心脏中产生的不同机械信号中，振荡流被认为是指示内皮细胞朝向瓣膜发生的重要因素，并导致klf 2a [4]（一种已知的动脉粥样硬化保护转录因子[5]）的表达。到目前为止，内皮细胞感受到流动力的机制还不清楚。在瓣膜形成初期，振荡流改变了产生的壁面切应力（WSS）的频谱，这是内皮细胞感受到的关键机械输入。在这里，我们建立了机械敏感性通道被激活，响应振荡流，并直接影响瓣膜形成，通过调节内皮细胞的反应。通过结合实时成像和数学建模，我们量化了阀门开发过程中WSS的振荡内容，并证明它设置了内皮细胞对流量的响应。此外，我们表明，endoorthodonium钙响应和流量响应klf 2a启动子调制的振荡流通过Trpv 4，机械敏感离子通道，特别是在心脏瓣膜发育过程中的endoorthodonium表达。我们对已知的Trpv 4伴侣Trpp 2进行了类似的观察，并表明缺乏Trpv 4或Trpp 2都会导致瓣膜缺陷。这项工作确定了一个主要的机械转导通路参与脊椎动物瓣膜的形成。
In vertebrates, heart pumping is required for cardiac morphogenesis and altering myocardial contractility leads to abnormal intracardiac flow forces and valve defects [1-3]. Among the different mechanical cues generated in the developing heart, oscillatory flow has been proposed to be an essential factor in instructing endocardial cell fate toward valvulogenesis and leads to the expression of klf2a [4], a known atheroprotective transcription factor [5]. To date, themechanism by which flow forces are sensed by endocardial cells is not well understood. At the onset of valve formation, oscillatory flows alter the spectrum of the generated wall shear stress (WSS), a keymechanical input sensed by endothelial cells. Here, we establish that mechanosensitive channels are activated in response to oscillatory flow and directly affect valvulogenesis by modulating the endocardial cell response. By combining live imaging and mathematical modeling, we quantify the oscillatory content of the WSS during valve development and demonstrate it sets the endocardial cell response to flow. Furthermore, we show that an endocardial calcium response and the flow-responsive klf2a promoter are modulated by the oscillatory flow through Trpv4, a mechanosensitive ion channel specifically expressed in the endocardium during heart valve development. We made similar observations for Trpp2, a known Trpv4 partner, and show that both the absence of Trpv4 or Trpp2 leads to valve defects. This work identifies a major mechanotransduction pathway involved during valve formation in vertebrates.