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DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis.
- Source :
-
Cellular Physiology & Biochemistry (Karger AG) . Apr2018, Vol. 46 Issue 2, p520-531. 12p. - Publication Year :
- 2018
-
Abstract
- <bold><italic>Background/Aims:</italic></bold> The mechanistic target of rapamycin (mTOR) signaling pathway is essential for angiogenesis and embryonic development. DEP domain-containing mTOR-interacting protein (DEPTOR) is an mTOR binding protein that functions to inhibit the mTOR pathway <italic>In vitro</italic> experiments suggest that DEPTOR is crucial for vascular endothelial cell (EC) activation and angiogenic responses. However, knowledge of the effects of DEPTOR on angiogenesis <italic>in vivo</italic> is limited. This study aimed to determine the role of DEPTOR in tissue angiogenesis and to elucidate the molecular mechanisms. <bold><italic>Methods:</italic></bold><italic>Cre/loxP</italic> conditional gene knockout strategy was used to delete the <italic>Deptor</italic> gene in mouse vascular ECs. The expression or distribution of cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1α) were detected by immunohistochemical staining or western blot. Tube formation assay was used to measure angiogenesis <italic>in vitro</italic>. <bold><italic>Results:</italic></bold><italic>Deptor</italic> knockdown led to increased expression of CD31, VEGF and HIF-1α in heart, liver, kidney and aorta. After treatment with rapamycin, their expression was significantly down regulated. <italic>In vitro</italic>, human umbilical vein endothelial cells (HUVECs) were transfected with DEPTOR-specific small interfering RNA (siRNA), which resulted in a significant increase in endothelial tube formation and migration rates. In contrast, DEPTOR overexpression markedly reduced the expression of CD31, VEGF and HIF-1α. <bold><italic>Conclusions:</italic></bold> Our findings demonstrated that deletion of the <italic>Deptor</italic> gene in vascular ECs resulted in upregulated expression of CD31 and HIF-1α, and further stimulated the expression of VEGF which promoted angiogenesis, indicating that disruption of normal angiogenic pathways may occur through hyperactivation of the mTORC1/HIF-1α/VEGF signaling pathway. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 10158987
- Volume :
- 46
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Cellular Physiology & Biochemistry (Karger AG)
- Publication Type :
- Academic Journal
- Accession number :
- 129340086
- Full Text :
- https://doi.org/10.1159/000488619