PDK1 regulates vascular remodeling and promotes epithelial-mesenchymal transition in cardiac development.
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.
Feng
Qiuting
Q
Department of Cardiology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Di
Ruomin
R
Tao
Fang
F
Chang
Zai
Z
Lu
Shuangshuang
S
Fan
Wenjing
W
Shan
Congjia
C
Li
Xinli
X
Yang
Zhongzhou
Z
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D017209:Apoptosis; D001283:Atrioventricular Node / Q000002:abnormalities / Q000196:embryology / Q000201:enzymology; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D046149:Embryo Culture Techniques; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology; D004848:Epithelium / Q000196:embryology / Q000201:enzymology; D005260:Female; D005318:Fetal Heart / Q000196:embryology* / Q000201:enzymology*; D006330:Heart Defects, Congenital / Q000196:embryology / Q000201:enzymology / Q000235:genetics; D006351:Heart Valves / Q000002:abnormalities / Q000196:embryology / Q000201:enzymology; D008648:Mesoderm / Q000196:embryology / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism
D017931:DNA Primers; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
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