PDK1 Regulates Vascular Remodeling and Promotes Epithelial-Mesenchymal Transition in Cardiac Development
PDK1 Regulates Vascular Remodeling and Promotes Epithelial-Mesenchymal Transition in Cardiac Development
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DOI：
10.1128/mcb.00420-10
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发表时间：
2010-07-01
影响因子：
5.3
通讯作者：
Yang, Zhongzhou
中科院分区：
文献类型：
--
作者：
Feng, Qiuting;Di, Ruomin;Yang, Zhongzhou
受体酪氨酸激酶（RTK）（例如血管内皮生长因子受体（VEGFR）和Tie 2受体）的一种必需下游信号传导途径是磷酸肌醇-3激酶（PI 3 K）-磷酸肌醇依赖性蛋白激酶1（PDK 1）-Akt/蛋白激酶B（PK B）级联，其在发育和肿瘤发生中起关键作用。然而，PDK 1在心血管发育中的作用仍然未知。在这里，我们在小鼠的内皮细胞中特异性地删除了PDK 1。这些小鼠表现出出血和心包积液，并在大约胚胎第11.5天（E11.5）死亡。组织学分析显示血管重塑和发育缺陷，心脏内皮和小梁/心肌之间的完整性被破坏。房室管（AVC）垫和瓣膜未能形成，表明上皮间质转化（EMT）缺陷，以及内皮细胞凋亡增加。一致地，离体AVC外植体培养显示间充质生长受阻。在AVC细胞中，Snail蛋白减少，并且不在细胞核中。将Snail S6 A突变体递送至AVC外植体有效地挽救了EMT缺陷。此外，腺病毒Akt递送挽救了AVC外植体培养物中的EMT缺陷，并且PTEN的缺失将PDK 1内皮缺失小鼠的胚胎死亡延迟1天，并使PDK 1缺陷心脏中的AVC垫正常发育。总之，这些结果揭示了PDK 1通过激活Akt和Snail在心血管发育中的重要作用。
One essential downstream signaling pathway of receptor tyrosine kinases (RTKs), such as vascular endothelial growth factor receptor ( VEGFR) and the Tie2 receptor, is the phosphoinositide-3 kinase (PI3K)-phosphoinositide-dependent protein kinase 1 (PDK1)-Akt/protein kinase B (PKB) cascade that plays a critical role in development and tumorigenesis. However, the role of PDK1 in cardiovascular development remains unknown. Here, we deleted PDK1 specifically in endothelial cells in mice. These mice displayed hemorrhage and hydropericardium and died at approximately embryonic day 11.5 (E11.5). Histological analysis revealed defective vascular remodeling and development and disrupted integrity between the endothelium and trabeculae/myocardium in the heart. The atrioventricular canal (AVC) cushion and valves failed to form, indicating a defect in epithelial-mesenchymal transition (EMT), together with increased endothelial apoptosis. Consistently, ex vivo AVC explant culture showed impeded mesenchymal outgrowth. Snail protein was reduced and was absent from the nucleus in AVC cells. Delivery of the Snail S6A mutant to the AVC explant effectively rescued EMT defects. Furthermore, adenoviral Akt delivery rescued EMT defects in AVC explant culture, and deletion of PTEN delayed embryonic lethality of PDK1 endothelial deletion mice by 1 day and rendered normal development of the AVC cushion in the PDK1-deficient heart. Taken together, these results have revealed an essential role of PDK1 in cardiovascular development through activation of Akt and Snail.