Akt1 promotes stimuli-induced endothelial-barrier protection through FoxO-mediated tight-junction protein turnover
| العنوان: | Akt1 promotes stimuli-induced endothelial-barrier protection through FoxO-mediated tight-junction protein turnover |
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| المؤلفون: | Sandeep Artham, Ahmad Al-Azayzih, Ralf H. Adams, Xiao Ding Peng, Payaningal R. Somanath, Harika Sabbineni, Tatiana V. Byzova, Nissim Hay, Fei Gao |
| المصدر: | Cellular and Molecular Life Sciences. 73:3917-3933 |
| بيانات النشر: | Springer Science and Business Media LLC, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Vascular Endothelial Growth Factor A, 0301 basic medicine, Time Factors, Mice, Transgenic, Vascular permeability, Biology, Article, Tight Junctions, Capillary Permeability, Adherens junction, Glycogen Synthase Kinase 3, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Angiopoietin-1, Animals, Humans, Claudin-5, Claudin, Molecular Biology, Pharmacology, Tight junction, Forkhead Box Protein O3, Endothelial Cells, Adherens Junctions, Cell Biology, Cell biology, Vascular endothelial growth factor B, Vascular endothelial growth factor, Vascular endothelial growth factor A, 030104 developmental biology, Vascular endothelial growth factor C, chemistry, 030220 oncology & carcinogenesis, Microvessels, embryonic structures, Cancer research, Molecular Medicine, Proto-Oncogene Proteins c-akt |
| الوصف: | Vascular permeability regulated by the vascular endothelial growth factor (VEGF) through endothelial-barrier junctions is essential for inflammation. Mechanisms regulating vascular permeability remain elusive. Although ‘Akt’ and ‘Src’ have been implicated in the endothelial-barrier regulation, it is puzzling how both agents that protect and disrupt the endothelial-barrier activate these kinases to reciprocally regulate vascular permeability. To delineate the role of Akt1 in endothelial-barrier regulation, we created endothelial-specific, tamoxifen-inducible Akt1 knockout mice and stable ShRNA-mediated Akt1 knockdown in human microvascular endothelial cells. Akt1 loss leads to decreased basal and angiopoietin1-induced endothelial-barrier resistance, and enhanced VEGF-induced endothelial-barrier breakdown. Endothelial Akt1 deficiency resulted in enhanced VEGF-induced vascular leakage in mice ears, which was rescued upon re-expression with Adeno-myrAkt1. Furthermore, co-treatment with angiopoietin1 reversed VEGF-induced vascular leakage in an Akt1-dependent manner. Mechanistically, our study revealed that while VEGF-induced short-term vascular permeability is independent of Akt1, its recovery is reliant on Akt1 and FoxO-mediated claudin expression. Pharmacological inhibition of FoxO transcription factors rescued the defective endothelial-barrier due to Akt1 deficiency. Here we provide novel insights on the endothelial-barrier protective role of VEGF in the long-term and the importance of Akt1-FoxO signaling on tight-junction stabilization and prevention of vascular leakage through claudin expression. |
| تدمد: | 1420-9071 1420-682X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0f00c7e3bc289bc5872dfb53f9601bd8Test https://doi.org/10.1007/s00018-016-2232-zTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0f00c7e3bc289bc5872dfb53f9601bd8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14209071 1420682X |
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