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

马的早期妊娠丢失是马业繁殖效率低下和经济损失的重要原因。据报道，部分原因与母亲未能识别妊娠有关。MRP是一个涉及一系列复杂事件的过程，这些事件允许母马对胚胎的存在做出反应，从而维持黄体（CL）和持续分泌孕酮。在母马中，MRP的细节仍然难以捉摸，但人们认识到，它涉及一个复杂的信号级联反应。在反刍动物中，24 kDa的孕体滋养层产物干扰素tau（INFT）是MRP的起始物。在子宫内膜外植体模型中，已鉴定出1-10 kDa的马孕体物质可改变前列腺素（PG）的合成，但其作用机制尚不清楚。越来越多的实验证据表明，小肽激素、催产素和催产素偶联受体事件，例如前列腺素H2合酶（PGHS 2）的诱导，是母马MRP的关键调节因子。PGHS 2酶将花生四烯酸代谢为前列腺素F2-α，即母马体内假定的黄体溶解素。母马的垂体后叶系统性释放催产素，子宫内膜上皮局部合成催产素。与其他物种不同，催产素没有卵巢来源。催产素的生物半衰期很短。据信，母马体内催产素的全身和组织水平受到严格调节，因为这种激素参与重要的生理过程，例如：性唤起、子宫活动、MRP、分娩、母性行为和排奶。目前缺乏关于系统释放或局部产生的子宫内膜催产素如何相互作用或代谢的知识。据报道，催产素主要以旁分泌方式发挥作用。在其他物种中，“催产素酶”存在于血清中，并且存在具有膜结合催产素酶/胰岛素调节的氨肽酶的组织，其降解激素。有证据表明，在大多数物种中，催产素与其受体结合也会刺激催产素酶的活性。我建议研究催产素受体结合之间的关系，催产素的分泌，催产素代谢的母马在MRP的时间。母马使用催产素的途径、持续时间、使用的类似物和剂量会对黄体功能产生不同的结果，从没有影响到黄体期缩短或延长。为了理解这些催产素相关的作用，我将研究来自以下的子宫内膜和黄体组织：妊娠子宫内膜、催产素或催产素类似物（卡贝缩宫素）治疗的子宫内膜和黄体组织，以及第15天的非妊娠子宫内膜。我还将在与MRP相关的关键时间点（周期的第8 - 15天）检查妊娠和非妊娠患者的子宫内膜和黄体组织。我将用放射自显影术描述妊娠状态、排卵后天数和组织催产素酶位置之间的关系。我将确定血清和组织催产素酶的活性，并评估催产素、催产素酶和其他关键激素、受体和酶（如与前列腺素级联相关的酶）在生殖组织中的表达。了解与MRP相关的关键过程将使兽医更好地了解马的妊娠成功和失败，并将有助于开发更好的治疗干预措施，以防止妊娠丢失，并提高生殖效率。这项研究有助于确保马的生殖健康所必需的基本知识。

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.