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Premenstrual Regulation of the Pro-Angiogenic Factor CYR61 in Human Endometrium

Institute of Anatomy (I.G., S.S., E.W.) and Department of Obstetrics and Gynaecology (C.B., R.K.), University of Duisburg-Essen, 45122 Essen, Germany

Address all correspondence and requests for reprints to: Isabella Gashaw, Institut für Anatomie II, Universitätsklinikum Essen, Hufelandstr. 55, 45122 Essen, Germany. E-mail: isabella.gashaw{at}uk-essen.de.

The pro-angiogenic factor cysteine-rich protein 61 (CYR61/CCN1) mediates different signals in tumorigenesis, angiogenesis and is involved in the pathogenesis of endometriosis. In this study we investigated the temporal and spatial expression pattern in human endometrium during the menstrual cycle and its possible regulation mechanisms in the premenstrual phase. CYR61 transcript expression showed two distinct periods of elevated levels in the proliferative phase and in menstrual effluents. Because the menstrual breakdown of the functionalis is triggered by cytokines, prostaglandins (PGs), as well as hypoxia, we used a benign endometrial cell line to investigate if CYR61 is regulated by these factors. Hypoxic conditions transiently induced CYR61 mRNA levels and enhanced the secretion of the CYR61 protein into the medium. The hypoxia-inducible factor (HIF) 1 mediated this effect on CYR61 as evidenced by dimethyloxalylglycine treatment and by HIF1 short interfering RNA. CYR61 mRNA expression was further regulated by IL-1, TNF, PGE2, and PGF2. In addition, TNF and PGE2 elevated significantly CYR61 cellular protein levels in well-oxygenated cells but had only a slight effect on the quantity of secreted protein. Moreover, PGE2 combined with hypoxic conditions increased CYR61 mRNA and protein levels synergistically, whereas the combination with TNF abolished the CYR61 levels induced by hypoxia. Together, the up-regulation of CYR61 by hypoxia via HIF1, TNF, and PGE2 could represent possible mechanisms for the CYR61 increase at the onset of menstruation. The opposite effect of TNF combined with hypoxia on CYR61 up-regulation could contribute to a balanced expression level of this angiogenic factor in the endometrium.