Transcriptional regulation of VEGF expression by estrogen-related receptor γ

Vascular endothelial growth factor (VEGF) is associated with endothelial cell proliferation, migration and angiogenesis. Estrogen-related receptor gamma (ERR gamma) plays important regulatory roles in-fatty acid oxidation, mitochondrial biogenesis and gluconeogenesis. Recently, ERR gamma has been shown to be involved in angiogenesis; however, the mechanism of ERR gamma-mediated angiogenesis is poorly understood. Here the results show that ERR gamma activates VEGF gene transcription via two putative estrogen-related receptor binding elements (ERREs) mapped to the promoter region. Chromatin immunoprecipitation assays confirmed that ERR gamma hinds to the identified liRREs. Adenovims-mediated overexpression of ERR gamma increased the expression of VEGF gene and induced an increase, in VEGF secretion in C2C12 myotubes. In contrast, the secretion of VEGF was significantly decreased in the presence of the ERRy inverse agonist GSK5182. Furthermore, treatment of human umbilical vein endothelial cells (HUVECO with the conditioned medium from ERR gamma-overexpressing C2C12 myotubes significantly, increased proliferation, migration and tube formation. These data indicate that VEGF functions as a downstream target gene of ERR gamma and mediates the effects of ERR gamma on endothelial cells proliferation, migration and angiogenesis. This physiological function of ERR gamma might provide a novel target for treatment of ischemic diseases. (C) 2013 Institute of Materia Modica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association. Production and hosting by Elsevier B.V. All rights reserved.