期刊
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
卷 96, 期 8, 页码 2475-2483出版社
ENDOCRINE SOC
DOI: 10.1210/jc.2010-2971
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资金
- Medical Research Council [G0600048]
- MRC [G1002033, G0600048] Funding Source: UKRI
- Medical Research Council [G0600048, G1002033] Funding Source: researchfish
Context: 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-2 alpha synthesis increases, causing spiral arteriole constriction. We hypothesized that progesterone withdrawal, PGF(2 alpha), and hypoxia increase vascular endothelial growth factor (VEGF), an endometrial repair factor. Design and Results: 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(2 alpha) or hypoxia (0.5% O-2) resulted in significant increases in VEGF mRNA and protein. VEGF was maximal when cells were cotreated with PGF(2 alpha) 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(2 alpha) 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 alpha (HIF-1 alpha) silencing with RNA interference suppressed hypoxia-induced VEGF expression in endometrial cells but did not alter PGF(2 alpha)-induced VEGF expression. Conclusions: Endometrial VEGF is increased at the time of endometrial repair. Progesterone withdrawal, PGF(2 alpha), and hypoxia are necessary for this perimenstrual VEGF expression. Hypoxia acts via HIF-1 alpha to increase VEGF, whereas PGF(2 alpha) acts in a HIF-1 alpha-independent manner. Hence, two pathways regulate the expression of VEGF during endometrial repair. (J Clin Endocrinol Metab 96: 2475-2483, 2011)
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