Abstract
Vascular endothelial growth factor (VEGF)-dependent angiogenesis plays a crucial role in the corpus leteum formation and their functional maintenances in mammalian ovaries. We recently reported that the activation of hypoxia-inducible factor (HIF)-1α signaling contributes to the regulation of VEGF expression in the luteal cells (LCs) in response to hypoxia and human chorionic gonadotropin (HCG). This study was designed to test the hypothesis that, HIF prolyl-dydoxylases (PHDs) express in LCs and overexpression of PHD attenuates the expression of VEGF induced by HCG in LCs. By real-time PCR and western blot analysis, we examined the expression of PHDs, confirmed the plasmid transfection and their expression and also investigated the changes of HIF-1α and VEGF expression after treatment with HCG and PHD2 transgenes. PHD2 expression was significantly higher than the others, indicating its main roles. Moreover, a significant increase of VEGF mRNA was found after HCG treatment, while this increased VEGF mRNA was also blocked by PHD2 overexpression in LCs. Further analysis also found that, this HCG-induced increase of VEGF mRNA was consistent with the level of HIF-1α protein, which is regulated by HIF prolyl-dydoxylase -mediated degradation. Taken together, our results indicated that, PHD2 mainly expressed in LCs and HCG-induced VEGF expression can be blocked by PHD2 overexpression through HIF-1α -mediated mechanism in LCs. This PHD2-mediated transcriptional activation may be one of the important mechanisms regulating VEGF expression in LCs during mammalian corpus leteum development. Key words: Hypoxia-inducible factor-1α, HIF prolyl-dydoxylase, vascular endothelial growth factor, human chorionic gonadotropin, luteal cells.
Highlights
Vascular endothelial growth factor (VEGF) plays a fundamental role in the physiological angiogenesis and the vascularization of the follicular luteinizing granulosa layer during corpus luteum (CL) formation (ChristensonAbbreviations: VEGF, Vascular endothelial growth factor; HIF, hypoxia-inducible factor; HCG, human chorionic gonadotropin; PHDs, prolyl-dydoxylases; LC, luteal cells.and Stouffer, 1997; Kaczmarek et al, 2005; Shimizu et al, 2007a; Shimizu and Miyamoto, 2007b)
We recently reported that the activation of hypoxia-inducible factor (HIF)-1α signaling contributes to the regulation of VEGF expression in the luteal cells (LCs) in response to hypoxia and human chorionic gonadotropin (HCG)
Our results indicated that, PHD2 mainly expressed in LCs and HCG-induced VEGF expression can be blocked by PHD2 overexpression through HIF-1α -mediated mechanism in LCs
Summary
Vascular endothelial growth factor (VEGF) plays a fundamental role in the physiological angiogenesis and the vascularization of the follicular luteinizing granulosa layer during corpus luteum (CL) formation (Christensonand Stouffer, 1997; Kaczmarek et al, 2005; Shimizu et al, 2007a; Shimizu and Miyamoto, 2007b). Vascular endothelial growth factor (VEGF) plays a fundamental role in the physiological angiogenesis and the vascularization of the follicular luteinizing granulosa layer during corpus luteum (CL) formation Because inhibition of VEGF in vivo during the luteal phase will prevent luteal angiogenesis and subsequent progesterone secretion (Duncan et al, 2008; Fraser et al, 2005; Fraser et al, 2006; Wulff et al, 2001), the excess VEGF generation during the vascularization of multiple follicles is thought to cause ovarian hyperstimulation syndrome (OHSS) (Nastri et al, 2010; Neulen et al, 1995; Zhang et al, 2010a). The molecular regulation of luteal VEGF expression becomes more and more important.
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