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The regulation of vascular endothelial growth factor by hypoxia and prostaglandin F?? during human endometrial repair.

ABSTRACT: The human endometrium has an exceptional capacity for repeated repair after menses, but its regulation remains undefined. Premenstrually, progesterone levels fall and prostaglandin (PG) F?? synthesis increases, causing spiral arteriole constriction. We hypothesized that progesterone withdrawal, PGF??, and hypoxia increase vascular endothelial growth factor (VEGF), an endometrial repair factor.Endometrial biopsies were collected (n = 47) with ethical approval and consent. VEGF mRNA, quantified by quantitative RT-PCR, was increased during menstruation (P < 0.01).VEGF protein was maximally secreted from proliferative endometrial explants. Treatment of an endometrial epithelial cell line and primary human endometrial stromal cells with 100 nm PGF?? or hypoxia (0.5% O?) resulted in significant increases in VEGF mRNA and protein. VEGF was maximal when cells were cotreated with PGF(2?) and hypoxia simultaneously (P < 0.05-0.001). Secretory-phase endometrial explants also showed an increase in VEGF with cotreatment (P < 0.05). However, proliferative-phase explants showed no increase in VEGF on treatment with PGF?? and/or hypoxia. Proliferative tissue was induced to increase VEGF mRNA expression when exposed to progesterone and its withdrawal in vitro but only in the presence of hypoxia and PG. Hypoxia-inducible factor-1? (HIF-1?) silencing with RNA interference suppressed hypoxia-induced VEGF expression in endometrial cells but did not alter PGF??-induced VEGF expression.Endometrial VEGF is increased at the time of endometrial repair. Progesterone withdrawal, PGF??, and hypoxia are necessary for this perimenstrual VEGF expression. Hypoxia acts via HIF-1? to increase VEGF, whereas PGF?? acts in a HIF-1?-independent manner. Hence, two pathways regulate the expression of VEGF during endometrial repair.

SUBMITTER: Maybin JA

PROVIDER: S-EPMC3380090 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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The regulation of vascular endothelial growth factor by hypoxia and prostaglandin F₂α during human endometrial repair.

Maybin Jacqueline A JA Hirani Nikhil N Brown Pamela P Jabbour Henry N HN Critchley Hilary O D HO

The Journal of clinical endocrinology and metabolism 20110615 8

<h4>Context</h4>The human endometrium has an exceptional capacity for repeated repair after menses, but its regulation remains undefined. Premenstrually, progesterone levels fall and prostaglandin (PG) F₂α synthesis increases, causing spiral arteriole constriction. We hypothesized that progesterone withdrawal, PGF₂α, and hypoxia increase vascular endothelial growth factor (VEGF), an endometrial repair factor.<h4>Design and results</h4>Endometrial biopsies were collected (n = 47) with ethical app ...[more]

PMID: 21677035

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Project description:Vascular endothelial growth factor (VEGF) and endometrial angiogenesis play a critical role in successful embryonic implantation. Despite many studies of the effects of estrogen and progesterone on VEGF expression, its focal regulation at the site of implantation is unknown. Retinoic acid (RA) has been reported to regulate VEGF in a variety of cell types. Because localized RA synthesis occurs within the periimplantation endometrium, we tested the possibility that RA regulates VEGF production in endometrial stromal cells. Using primary and telomerase-immortalized human endometrial stromal cells, we determined that RA alone did not alter constitutive levels of VEGF production, but markedly amplified secretion when the cells were cotreated with activators of VEGF gene transcription (12-O-tetradecanoyl phorbol-13-acetate, TPA; TGF-beta; and IL-1beta). Whereas TPA or TGF-beta alone stimulated VEGF promoter activity and up-regulated mRNA levels, significant protein secretion was detected only after RA was added to the culture systems. Analysis of retinoids in secretory phase endometrial biopsies indicated that endogenous RA accumulated at concentrations sufficient to induce VEGF secretion. Polyribosome profile analysis showed that the addition of RA to transcriptional activators of VEGF shifted the translational suppressed VEGF mRNA transcripts into larger polyribosome complexes engaged in active translation. Although the precise mechanism(s) of the RA effect remains to be defined, it appears to be mediated by reactive oxygen species; the antioxidant N-acetylcysteine inhibited RA+TPA-stimulated secretion of VEGF by more than 80%. Together, our results demonstrate that in human endometrial stromal cells, RA can combine with transcriptional activators of VEGF to augment VEGF secretion through a translational mechanism of action mediated by reactive oxygen species. These findings suggest a link between the spatiotemporal changes of retinoid synthesis in the periimplantation stroma and the capacity to quickly up-regulate focal VEGF secretion needed to induce early angiogenic events of pregnancy.

Dataset Information

The regulation of vascular endothelial growth factor by hypoxia and prostaglandin F?? during human endometrial repair.

Publications

The regulation of vascular endothelial growth factor by hypoxia and prostaglandin F₂α during human endometrial repair.

Similar Datasets

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