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Hypoxia-Inducible Factor-1 Expression in Human Endometrium and Its Regulation by Prostaglandin E-Series Prostanoid Receptor 2 (EP2)

University of Edinburgh (H.O.D.C., J.O., T.A.H., L.B.), Centre for Reproductive Biology, The Queen’s Medical Research Institute, and Medical Research Council Human Reproductive Sciences Unit (K.J.S., H.N.J.), The Queen’s Medical Research Institute, Edinburgh EH16 4TJ, Scotland, United Kingdom; and Medical Research Council Centre for Inflammation Research (N.H.), University of Edinburgh, Edinburgh EH8 9AG, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Professor Hilary O. D. Critchley, University of Edinburgh, Centre for Reproductive Biology, The Queen’s Medical Research Building, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom. E-mail: hilary.critchley{at}ed.ac.uk.

The menstrual cycle is a complex interaction of sex steroids, prostanoids, and cytokines that lead to coordinated tissue degradation, regeneration and repair. The transcription factor hypoxia-inducible factor (HIF-1) plays critical roles in cellular responses to hypoxia, the generation of an inflammatory response and vasculogenesis through transcriptional activation of angiogenic genes. We hypothesize that HIF-1 is expressed in human endometrium and that locally synthesized prostaglandins (PGE2 and PGF₂) regulate HIF-1 activity. Here we demonstrate that PGE2 up-regulates HIF-1 mRNA and protein via the E-series prostanoid receptor 2 (EP2), and this up-regulation is dependent on epidermal growth factor receptor kinase activity. We show the tight temporal-spatial confinement of HIF-1 protein expression in endometrium across the cycle. HIF-1 is expressed exclusively during the secretory and menstrual phases. Protein expression is maximal at progesterone withdrawal during the late secretory and menstrual phase. HIF-1 protein colocalizes with prostaglandin EP2 receptor in glandular cells. In contrast, HIF-1ß/aryl receptor nuclear translocator 1 expression occurs throughout the cycle but is maximal in glandular cells during the proliferative phase. This provides evidence for a role for HIF-1 in the menstrual cycle and demonstrates that HIF-1 activation in human endometrium may occur via a PGE2-regulated pathway and provides a coordinated pathway from progesterone withdrawal through to angiogenic gene expression via HIF-1.

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