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J Clin Endocrinol Metab. 2011 Aug;96(8):2475-83. doi: 10.1210/jc.2010-2971. Epub 2011 Jun 15.

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

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  • 1Centre for Reproductive Biology, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.



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.


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 PGF₂α or hypoxia (0.5% O₂) resulted in significant increases in VEGF mRNA and protein. VEGF was maximal when cells were cotreated with PGF(2α) 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 PGF₂α 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-1α (HIF-1α) silencing with RNA interference suppressed hypoxia-induced VEGF expression in endometrial cells but did not alter PGF₂α-induced VEGF expression.


Endometrial VEGF is increased at the time of endometrial repair. Progesterone withdrawal, PGF₂α, and hypoxia are necessary for this perimenstrual VEGF expression. Hypoxia acts via HIF-1α to increase VEGF, whereas PGF₂α acts in a HIF-1α-independent manner. Hence, two pathways regulate the expression of VEGF during endometrial repair.

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