Vascular endothelial growth factor suppresses TNFSF15 production in endothelial cells by stimulating miR-31 and miR-20a expression via activation of Akt and Erk signals.
FEBS Open Bio
; 7(1): 108-117, 2017 01.
Article
em En
| MEDLINE
| ID: mdl-28097093
ABSTRACT
Tumor necrosis factor superfamily-15 (TNFSF15; VEGI; TL1A) is a negative modulator of angiogenesis for blood vessel homeostasis and is produced by endothelial cells in a mature vasculature. It is known to be downregulated by vascular endothelial growth factor (VEGF), a major regulator of neovascularization but the mechanism of this interaction is unclear. Here we report that VEGF is able to stimulate the production of two microRNAs, miR-20a and miR-31, which directly target the 3'-UTR of TNFSF15. Additionally, we show that two VEGF-stimulated cell growth signals, Erk and Akt, are responsible for promoting the expression of miR-20a and miR-31. Treatment of human umbilical vein endothelial cells (HUVECs) with Akt inhibitor LY294002 results in diminished miR-20a and miR-31 production, while Erk inhibitor U0126 prevented VEGF-stimulated expression of miR-20a but not that of miR-31. Furthermore, inactivation of either Erk or Akt signals restores TNFSF15 gene expression. In an angiogenesis assay, elevated miR-20a or miR-31 levels in HUVECs leads to enhancement of capillary-like tubule formation in vitro, whereas lowered miR-20a and miR-31 levels results in an inhibition. These findings are consistent with the view that miR-20a and miR-31 mediate VEGF-induced downregulation of TNFSF15. Targeting these microRNA molecules may therefore provide an effective approach to inhibit angiogenesis.
Texto completo:
1
Base de dados:
MEDLINE
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article