Cellular Transport of Prostaglandins in the Ovine Uterus

In ruminants, prostaglandin F2 alpha (PGF2?) is released from the endometrium in a pulsatile pattern at the time of luteolysis. The luteolytic PGF2? pulses are transported from the uterus to the corpus luteum (CL) through the utero-ovarian plexus (UOP) to cause luteolysis. At the time of establishment of pregnancy, interferon tau (IFNT) secreted by the conceptus suppresses the pulsatile release of PGF2? and thereby rescues the CL and maintains its secretion of progesterone. However, basal concentrations of PGF2? are higher in pregnant ewes than in cyclic ewes. The pulsatile release of PGF2? likely requires selective carrier-mediated transport and cannot be supported by a simple diffusion mechanism. The molecular and functional aspects of carrier mediated transport of PGF2? from the uterus to the ovary through the utero- ovarian plexus (UOP) at the time of luteolysis and recognition/establishment of pregnancy are largely unknown ruminants.

Results indicate that intrauterine inhibition of (PGT) prevents the pulsatile release of PGF2? independently of spatial expressions of estrogen receptor (ESR-1) and oxytocin receptor (OXTR) proteins by the endometrium at the time of luteolysis in sheep. PGT protein is expressed in the UOP during the estrous cycle and pharmacological inhibition of PGT prevents transport of luteolytic PGF2? pulse through the UOP in sheep. IFNT activates novel JAK-SRC-EGFR-RAS-RAF-ERK1/2-EGR-1 signaling modules in endometrial luminal epithelial (LE) cells and regulates PGT- mediated release of PGF2? through these novel cell-signaling pathways. IFNT stimulates ERK1/2 pathways in endometrial LE cells and inhibition of ERK1/2 inhibits IFNT action and restores spatial expression of OXTR and ESR-1 proteins in endometrial LE cells and restores endometrial luteolytic pulses of PGF2? in sheep.

Collectively, the results of the present study provide the first evidence to indicate that transport of endometrial luteolytic PGF2? pulses from the uterus to the ovary through the UOP is controlled by a PGT-mediated mechanism in sheep, new mechanistic insight into molecular mechanisms regulating cellular and compartmental transport of PGF2? at the time of luteolysis, and new mechanistic understanding of IFNT action and release of PGF2? from the endometrial LE cells and thus opens a new arena of research in IFNT signaling and PGT function.