Downregulation of ERRα inhibits angiogenesis in human umbilical vein endothelial cells through regulating VEGF production and PI3K/Akt/STAT3 signaling pathway

The human estrogen related receptor alpha (ERR alpha) is a pivotal regulator involved in energy homeostasis and mitochondrial biogenesis. It has been demonstrated that activation of ERR alpha in various breast cancer cells results in a significant increase of vascular endothelial growth factor (VEGF) mRNA and protein secretion. However, little is known about the relationship between ERRoc and angiogenesis. Thus, the present study is aimed to investigate the effects and mechanism of ERR alpha suppression on the angiogenesis in human umbilical vein endothelial cells (HUVECs). Here we show that ERR alpha suppression powerfully inhibits proliferation, migration and capillary-like structures formation of HUVECs. Importantly, we demonstrate that these inhibitory effects are associated with the significantly reduced expression and production of VEGF. Results from further experiments using western blot and luciferase reporter assay exhibit that ERR alpha suppression inhibits hypoxia-inducible factor 1 alpha (HIF-1 alpha) expression, and phosphorylation of protein kinase B (Akt) and signal transducer and activator of transcription (STAT3) which up-regulated VEGF expression. In summary, we show that ERR alpha suppression inhibits angiogenesis in HUVECs and deserves further studies for application of rationale therapeutic target for patient with diseases related with aberrant angiogenesis. (C) 2015 Elsevier B.V. All rights reserved.