PDK1 Regulates Vascular Remodeling and Promotes Epithelial-Mesenchymal Transition in Cardiac Development
| Autor: | Ruo-Min Di, Wenjing Fan, Fang Tao, Zai Chang, Qiuting Feng, Xinli Li, Shuangshauang Lu, Congjia Shan, Zhongzhou Yang |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Heart Defects
Congenital animal structures Endothelium Apoptosis Protein Serine-Threonine Kinases Epithelium Receptor tyrosine kinase 3-Phosphoinositide-Dependent Protein Kinases Embryo Culture Techniques Mesoderm Mice Fetal Heart Pregnancy medicine Animals PTEN Epithelial–mesenchymal transition Protein kinase A Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway DNA Primers Mice Knockout Base Sequence biology PTEN Phosphohydrolase Endothelial Cells Articles Cell Biology Heart Valves Cell biology Mice Inbred C57BL medicine.anatomical_structure embryonic structures Immunology Atrioventricular Node biology.protein Female Snail Family Transcription Factors Signal transduction Proto-Oncogene Proteins c-akt Signal Transduction Transcription Factors |
| Zdroj: | Molecular and Cellular Biology. 30:3711-3721 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.00420-10 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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