Uterine biology in pigs and sheep

Abstract

There is a dialogue between the developing conceptus (embryo-fetus and associated placental membranes) and maternal uterus which must be established during the peri-implantation period for pregnancy recognition signaling, implantation, regulation of gene expression by uterine epithelial and stromal cells, placentation and exchange of nutrients and gases. The uterus provide a microenvironment in which molecules secreted by uterine epithelia or transported into the uterine lumen represent histotroph required for growth and development of the conceptus and receptivity of the uterus to implantation. Pregnancy recognition signaling mechanisms sustain the functional lifespan of the corpora lutea (CL) which produce progesterone, the hormone of pregnancy essential for uterine functions that support implantation and placentation required for a successful outcome of pregnancy. It is within the peri-implantation period that most embryonic deaths occur due to deficiencies attributed to uterine functions or failure of the conceptus to develop appropriately, signal pregnancy recognition and/or undergo implantation and placentation. With proper placentation, the fetal fluids and fetal membranes each have unique functions to ensure hematotrophic and histotrophic nutrition in support of growth and development of the fetus. The endocrine status of the pregnant female and her nutritional status are critical for successful establishment and maintenance of pregnancy. This review addresses the complexity of key mechanisms that are characteristic of successful reproduction in sheep and pigs and gaps in knowledge that must be the subject of research in order to enhance fertility and reproductive health of livestock species.

Figure 1

[A] Oöcytes fertilized in the oviduct enter the uterus at the morula stage, hatch from the zona pellucida as spherical blastocysts and then transition to large spherical, tubular and filamentous conceptuses (embryo and its extra-embryonic membranes) with interferon tau (IFNT), the pregnancy recognition signal, being secreted from mononuclear trophectoderm cells between Days 10 and 21 of pregnancy.[B] Endometrial epithelia cease expressing receptors for progesterone (PGR) due to autoregulation by progesterone and IFNT silences expression of receptors for estradiol (ESR1) and oxytocin receptors (OXTR) to abrogate development of the mechanism for oxytocin-mediated pulsatile release of prostaglandin F_2α (PGF) which would otherwise cause regression of the corpus luteum and cessation of progesterone secretion. The endometrial stromal fibroblasts express PGR and secrete fibroblast growth factor 10 that regulates uterine epithelia cell function. With down-regulation of PGR in uterine epithelia the uterine luminal (LE) and superficial glandular (sGE) epithelia express genes that are either induced by progesterone (P4) or induced by P4 and further stimulated by IFNT. Further, IFNT induces expression of interferon regulatory factor 2 (IRF2) in uterine LE and sGE to silence expression of classical interferon stimulated genes and allow expression of a unique set of genes that promote conceptus growth and development. The endometrial glandular epithelial cells (GE) and stromal fibroblasts do not express IRF2 and, therefore, express classical interferon stimulated proteins. Collectively, molecules secreted by uterine epithelia or transported into the uterine lumen by uterine epithelia form histotroph required for conceptus development. [C] The ovine conceptus undergoes the adhesion cascade for implantation.

Figure 2

Histotroph includes molecules secreted or transported into the uterine lumen to stimulate growth and development of the conceptus during the peri-implantation period and for the duration of pregnancy in species with epitheliochorial and syndesmochorial placentae. The uterine luminal (LE) and superficial glandular (sGE) epithelia (blue color) in closest proximity to trophectoderm express novel genes in response to progesterone and interferon tau that support conceptus development in ewes. The uterine glandular (GE) and stromal cells express classical interferon stimulated genes during the peri-implantation period of pregnancy.

Figure 3

Silencing expression of progesterone receptor (PGR) and signal transducer and activator of transcription facor 1 (STAT1) in uterine luminal (LE) and superficial glandular (sGE) epithelia is a prerquisite for implantation in mammals. Therefore, progesterone acts via PGR-positive uterine stromal cells to increase expression of fibroblast growth factor-7 (FGF7) and FGF10, and hepatocyte growth factor (HGF) in sheep uteri. These progestamedins and interferon tau (IFNT) then exert paracrine effects on uterine epithelia and conceptus trophectoderm to stimulate gene expression and secretory responses by trophectoderm and uterine LE and sGE.

Figure 4

[A] During pregnancy in ewes the increases in placental length and weight precede the period of rapid growth of the fetus during gestation because the placenta must be established to transport nutrients and gases to the conceptus to ensure it growth and survival.[B] The comparison of total amounts of glucose and fructose in allantoic fluid (ALF) fluid suggest that fructose is a major substrate for metabolism via the pentose phosphate pathway, hexosamine pathway and glycolytic pathways.

Figure 5

The hexosamine pathway allows for both glucose and fructose to be metabolized to glucosamine-6-phosphate that lead to activation of the MTOR cell signaling pathway, as well as synthesis of glycosaminoglycans such as hyaluronic acid, that are critical to growth and development of the conceptus.

Figure 6

Focal adhesions are dramatically upregulated in different tissue-level compartments within the uterus during pregnancy in response to continuous application of local force outside the cell balanced by cytoskeletal contraction. The different organization and size of these macromolecular assemblies containing cytoskeletal binding proteins, adapter proteins and signaling molecules illustrate how mechanical forces regulate the form and function of the uterine wall and also reveal markedly different elastic microenvironments.