The Role of Oxytocin and Oxytocinase in the Maternal Recognition of Pregnancy in Mares

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Early pregnancy loss in mares is a substantial cause of reproductive inefficiency and economic loss in the equine industry. It is reported to be partly related to a failure of the maternal recognition of pregnancy (MRP). MRP is a process that involves a series of complex and complicated events that allow a mare to respond to the presence of an embryo, resulting in maintenance of the corpus luteum (CL) and the continued secretion of progesterone. The details of MRP remain elusive in the mare but it is recognized that an intricate signaling cascade is involved. In ruminants a 24 kDa conceptus trophoblast product, interferon tau (INFT), is the initiator of the MRP. A 1-10 kDa equine conceptus substance has been identified that alters prostaglandin (PG) synthesis in an endometrial explant model, but the mechanism of action is unknown. Mounting experimental evidence shows that the small peptide hormone, oxytocin, and oxytocin coupled receptor events, such as induction of prostaglandin H2 synthase (PGHS2), are key regulators of the MRP in mares. The enzyme PGHS2 metabolizes arachidonic acid to Prostaglandin F2-alpha, the putative luteolysin in the mare. The mare has both systemically released oxytocin from the posterior pituitary and local synthesis of oxytocin in the endometrial epithelium. Unlike other species, there is no ovarian source of oxytocin. Oxytocin has a very short biologic half-life. The systemic and tissue levels of oxytocin are believed to be tightly regulated in the mare, as this hormone is involved in important physiologic processes such as: sexual arousal, uterine activity, MRP, parturition, maternal behaviour, and milk ejection. Currently there is a lack of knowledge of how systemically released or locally produced endometrial oxytocin interact or are metabolized. It is reported that oxytocin primarily functions in a paracrine fashion. In other species ‘oxytocinase’ is present in the serum and there are tissues that have a membrane bound oxytocinase/insulin regulated aminopeptidase that degrades the hormone. There is evidence of a negative feedback process in most species where oxytocin binding to its receptor also stimulates oxytocinase activity. I propose to study the relationship between oxytocin receptor binding, secretion of oxytocin, and metabolism of oxytocin in the mare around the time of MRP. The route, duration, analogue used and dose of oxytocin administered to mares results in different outcomes on luteal function, ranging from no effect to either a shortening or lengthening of the luteal phase. To understand these oxytocin related effects I will study endometrial and luteal tissues from: pregnant mares, oxytocin or oxytocin analog (carbetocin) treated mares, with non-pregnant mares at Day 15. I will also examine endometrial and luteal tissues of pregnant and non-pregnant mares at critical time points (day 8 -15 of the cycle) that are associated with the MRP. I will describe relationships between pregnancy status, number of days post ovulation and the location of tissue oxytocinases using autoradiography. I will determine the activity of serum and tissue oxytocinases, and evaluate the expression of oxytocin, oxytocinases, and other key hormones, receptors, and enzymes, such as those associated with the prostaglandin cascade, in reproductive tissues. An understanding of the critical processes associated with MRP will allow veterinarians a better understanding of pregnancy success and failure in horses and will enable the development of better therapeutic interventions to prevent pregnancy loss, and improve reproductive efficiency. This research contributes to fundamental knowledge essential to ensuring reproductive health in horses.