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Estradiol-17β, Prostaglandin E₂ (PGE₂), and the PGE₂ Receptor Are Involved in PGE₂ Positive Feedback Loop in the Porcine Endometrium

Institute of Animal Reproduction and Food Research of Polish Academy of Sciences (A.W., A.B., A.J.Z.), Tuwima 10, 10-747 Olsztyn, Poland; and Medical Research Council Human Reproductive Science Unit (H.N.J.), The Queens Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom

Address all correspondence and requests for reprints to: Agnieszka Waclawik, Institute of Animal Reproduction and Food Research of Polish Academy of Sciences, Tuwima 10, 10-747 Olsztyn, Poland. E-mail: waclawik{at}pan.olsztyn.pl.

Before implantation, the porcine endometrium and trophoblast synthesize elevated amounts of luteoprotective prostaglandin estradiol-17β (E₂) (PGE₂). We hypothesized that embryo signal, E₂, and PGE₂ modulate expression of key enzymes in PG synthesis: PG-endoperoxide synthase-2 (PTGS2), microsomal PGE synthase (mPGES-1), PGF synthase (PGFS), and PG 9-ketoreductase (CBR1) as well as PGE₂ receptor (PTGER2 and -4) expression and signaling within the endometrium. We determined the site of action of PGE₂ in endometrium during the estrous cycle and pregnancy. Endometrial tissue explants obtained from gilts (n = 6) on d 11–12 of the estrous cycle were treated with vehicle (control), PGE₂ (100 nM), E₂ (1–100 nM), or phorbol 12-myristate 13-acetate (100 nM, positive control). E₂ increased PGE₂ secretion through elevating expression of mPGES-1 mRNA and PTGS2 and mPGES-1 protein in endometrial explants. By contrast, E₂ decreased PGFS and CBR1 protein expression. E₂ also stimulated PTGER2 but not PTGER4 protein content. PGE₂ enhanced mPGES-1 and PTGER2 mRNA as well as PTGS2, mPGES-1, and PTGER2 protein expression. PGE₂ had no effect on PGFS, CBR1, and PTGER4 expression and PGF₂ release. Treatment of endometrial tissue with PGE₂ increased cAMP production. Cotreatment with PTGER2 antagonist (AH6809) but not PTGER4 antagonist (GW 627368X) inhibited significantly PGE₂-mediated cAMP production. PTGER2 protein was localized in luminal and glandular epithelium and blood vessels of endometrium and was significantly up-regulated on d 11–12 of pregnancy. Our results suggest that E₂ prevents luteolysis through enzymatic modification of PG synthesis and that E₂, PGE₂, and endometrial PTGER2 are involved in a PGE₂ positive feedback loop in porcine endometrium.