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

• Published in: European journal of pharmacology 2015-12, Vol.769, p.167-176
• Main Authors: Zhang, Liu-Di, Chen, Li, Zhang, Meng, Qi, Hui-Jie, Chen, Lu, Chen, Hai-Fei, Zhong, Ming-Kang, Shi, Xiao-Jin, Li, Qun-Yi
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Cell Movement; Cell Proliferation; Chick Embryo; Chorioallantoic Membrane - metabolism; Down-Regulation; ERRalpha Estrogen-Related Receptor; Estrogen related receptor α; Human umbilical vein endothelial cells; Human Umbilical Vein Endothelial Cells - cytology; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Migration; Neovascularization, Physiologic; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt; Receptors, Estrogen - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; STAT3 Transcription Factor - metabolism; Transcription Factors - genetics; Transcriptional Activation; Tube formation; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor A - genetics; VEGF
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2015.11.014

The human estrogen related receptor α (ERRα) is a pivotal regulator involved in energy homeostasis and mitochondrial biogenesis. It has been demonstrated that activation of ERRα 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 ERRα and angiogenesis. Thus, the present study is aimed to investigate the effects and mechanism of ERRα suppression on the angiogenesis in human umbilical vein endothelial cells (HUVECs). Here we show that ERRα 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 ERRα suppression inhibits hypoxia-inducible factor 1α (HIF-1α) 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 ERRα suppression inhibits angiogenesis in HUVECs and deserves further studies for application of rationale therapeutic target for patient with diseases related with aberrant angiogenesis.