Characterization of Hypoxia-Regulated Angiogenin Expression and Its Impact in Endometriosis

Abstract

Endometriosis characterized as the presence of endometrial tissues outside the uterus is one of the most common gynecological diseases in women of reproductive age Hypoxia plays important roles in promoting angiogenesis during the development of endometriosis However the underlying mechanism remains largely unknown Herein we identified angiogenin (ANG) a novel angiogenic factor is increased under hypoxia in endometriosis Since there is no hypoxia responsive element in the ANG promoter region we analyzed the potential transcription factor binding site in the promoter region of ANG and identified potential binding sites for chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) Downregulation of COUP-TFII is important for pathogenesis of endometriosis Thus we hypothesized that hypoxia regulates ANG expression via suppression of COUP-TFII in endometriosis Knockdown of COUP-TFII in eutopic endometrial stromal cells increased ANG expression Treatment of eutopic endometrial stromal cells with hypoxia decreased COUP-TFII expression and concomitantly induced ANG expression In contrast overexpression of COUP-TFII under hypoxia significantly reduced hypoxia-induced ANG expression Chromatin immunoprecipitation-qPCR analysis revealed that binding of COUP-TFII to ANG promoter region was significantly reduced under hypoxia Treatment with hypoxia or knockdown of COUP-TFII increased ANG promoter activity Treatment of human umbilical vein endothelial cells with conditioned media collected from stromal cells with COUP-TFII knockdown significantly promoted tube formation In contrast the COUP-TFII knockdown-induced angiogenic capacity was abolished by simultaneously knocking down of ANG Taken together our results demonstrated that ANG involves in the angiogenesis of endometriosis through hypoxia-mediated loss-of-COUP-TFII expression and suggest ANG may be a novel therapeutic target for treatment of endometriosis

Date of Award	2016 Feb 4
Original language	English
Supervisor	Shaw-Jenq Tsai (Supervisor)