Akt promotes endocardial-mesenchyme transition.
Akt promotes endocardial-mesenchyme transition.
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DOI：
10.1186/2040-2384-1-2
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发表时间：
2009-09-21
期刊：
影响因子：
--
通讯作者：
Benjamin LE
中科院分区：
文献类型：
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作者：
Meadows KN;Iyer S;Stevens MV;Wang D;Shechter S;Perruzzi C;Camenisch TD;Benjamin LE
在胚胎第9.5天（E9.5）发育中的心脏的心内膜、房室管（AVC）的内皮衬层形成心内膜垫的过程中，可以观察到内皮到间质的转变（EndMT）。该过程的许多监管机构已经确定；然而，驱动内皮细胞对 EndMT 的最初承诺决定的机制很难与间充质增殖和迁移所需的过程分开。我们有多项证据表明 Akt 信号传导在促使内皮细胞进入 EndMT 中发挥着核心作用。当心内膜垫形成时，Akt1 mRNA 仅限于心内膜。 PI3K/Akt 信号通路对于间质生长是必需的，因为用 PI3K 抑制剂 LY294002 处理的 AVC 外植体培养物中的发芽受到抑制。此外，内皮细胞中内皮细胞标记物 VE-钙粘蛋白下调，间质标记物 N-钙粘蛋白和 Snail 因内皮细胞中 Akt1 (myrAkt1) 组成型活性形式的表达而被诱导。最后，我们使用转基因模型分离了 Akt1 信号转导的功能，其中 myrAkt1 仅在心内膜细胞中脉冲，并在 EndMT 启动后关闭。通过这种方式，我们确定心内膜中增加的 Akt 信号传导驱动 EndMT，并削弱其在垫间充质细胞中的其他功能。
Endothelial to mesenchyme transition (EndMT) can be observed during the formation of endocardial cushions from the endocardium, the endothelial lining of the atrioventricular canal (AVC), of the developing heart at embryonic day 9.5 (E9.5). Many regulators of the process have been identified; however, the mechanisms driving the initial commitment decision of endothelial cells to EndMT have been difficult to separate from processes required for mesenchymal proliferation and migration. We have several lines of evidence that suggest a central role for Akt signaling in committing endothelial cells to enter EndMT. Akt1 mRNA was restricted to the endocardium of endocardial cushions while they were forming. The PI3K/Akt signaling pathway is necessary for mesenchyme outgrowth, as sprouting was inhibited in AVC explant cultures treated with the PI3K inhibitor LY294002. Furthermore, endothelial marker, VE-cadherin, was downregulated and mesenchyme markers, N-cadherin and Snail, were induced in response to expression of a constitutively active form of Akt1 (myrAkt1) in endothelial cells. Finally, we isolated the function of Akt1 signaling in the commitment to the transition using a transgenic model where myrAkt1 was pulsed only in endocardial cells and turned off after EndMT initiation. In this way, we determined that increased Akt signaling in the endocardium drives EndMT and discounted its other functions in cushion mesenchymal cells.