The regulation of vascular endothelial growth factor by hypoxia and prostaglandin F 2α during human endometrial repair

Abstract

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 2α synthesis increases, causing spiral arteriole constriction. We hypothesized that progesterone withdrawal, PGF 2α, 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 2α or hypoxia (0.5%O 2) 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 PGF 2α 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 PGF 2α-induced VEGF expression. Conclusions: Endometrial VEGF is increased at the time of endometrial repair. Progesterone withdrawal, PGF 2α, and hypoxia are necessary for this perimenstrual VEGF expression. Hypoxia acts via HIF-1α to increase VEGF, whereas PGF 2α acts in a HIF-1α-independent manner. Hence, two pathways regulate the expression of VEGF during endometrial repair. Copyright © 2011 by The Endocrine Society.