Pregnancy recognition signaling mechanisms in ruminants and pigs

Maternal recognition of pregnancy refers to the requirement for the conceptus（embryo and its associated extraembryonic membranes） to produce a hormone that acts on the uterus and/or corpus luteum（CL） to ensure maintenance of a functional CL for production of progesterone;the hormone required for pregnancy in most mammals.The pregnancy recognition signal in primates is chorionic gonadotrophin which acts directly on the CL via luteinizing hormone receptors to ensure maintenance of functional CL during pregnancy.In ruminants,interferon tau（IFNT） is the pregnancy recognition signal.IFNT is secreted during the peri-implantation period of pregnancy and acts on uterine epithelia to silence expression of estrogen receptor alpha and oxytocin receptor which abrogates the oxytocin-dependent release of luteolytic pulses of prostaglandin F2-alpha（PGF） by uterine epithelia;therefore,the CL continues to produce progesterone required for pregnancy.Pig conceptuses secrete interferon delta and interferon gamma during the peri-implantation period of pregnancy,but there is no evidence that they are involved in pregnancy recognition signaling.Rather,pig conceptuses secrete abundant amounts of estrogens between Days 11 to 15 of pregnancy required for maternal recognition of pregnancy.Estrogen,likely in concert with prolactin,prevents secretion of PGF into the uterine venous drainage（endocrine secretion）,but maintains secretion of PGF into the uterine lumen（exocrine secretion） where it is metabolized to a form that is not luteolytic.Since PGF is sequestered within the uterine lumen and unavailable to induce luteolysis,functional CL are maintained for production of progesterone.In addition to effects of chorionic gonadotrophin,IFNT and estrogens to signal pregnancy recognition,these hormones act on uterine epithelia to enhance expression of genes critical for growth and development of the conceptus.

Osteopontin: a leading candidate adhesion molecule for implantation in pigs and sheep

Osteopontin （OPN; also known as Secreted Phosphoprotein 1, SPP1） is a secreted extra-cellular matrix （ECM） protein that binds to a variety of cell surface integrins to stimulate cell-cell and cell-ECM adhesion and communication. It is generally accepted that OPN interacts with apically expressed integrin receptors on the uterine luminal epithelium （LE） and conceptus trophectoderm to attach the conceptus to the uterus for implantation. Research conducted with pigs and sheep has significantly advanced understanding of the role（s） of OPN during implantation through exploitation of the prolonged peri-implantation period of pregnancy when elongating conceptuses are free within the uterine lumen requiring extensive paracrine signaling between conceptus and endometrium. This is followed by a protracted and incremental attachment cascade of trophectoderm to uterine LE during implantation, and development of a true epitheliochorial or synepitheliochorial placenta exhibited by pigs and sheep, respectively. In pigs, implanting conceptuses secrete estrogens which induce the synthesis and secretion of OPN in adjacent uterine LE. OPN then binds to αvβ6 integrin receptors on trophectoderm, and the αvβ3 integrin receptors on uterine LE to bridge conceptus attachment to uterine LE for implantation. In sheep, implanting conceptuses secrete interferon tau that prolongs the lifespan of CL. Progesterone released by CL then induces OPN synthesis and secretion from the endometrial GE into the uterine lumen where OPN binds integrins expressed on trophectoderm （αvβ3） and uterine LE （identity of specific integrins unknown） to adhere the conceptus to the uterus for implantation. OPN binding to the αvβ3 integrin receptor on ovine trophectoderm cells induces in vitro focal adhesion assembly, a prerequisite for adhesion and migration of trophectoderm, through activation of： 1） P70S6K via crosstalk between FRAP1/MTOR and MAPK pathways; 2） MTOR, PI3K, MAPK3/MAPK1 （Erk1/2） and MAPK14 （p38） signaling to stimulate trohectoderm cell migration; and 3） focal adhesion assembly and myosin II motor activity to induce migration oftrophectoderm cells. Further large in vivo focal adhesions assemble at the uterine-placental interface of both pigs and sheep and identify the involvement of sizable mechanical forces at this interface during discrete periods of trophoblast migration, attachment and placentation in both species.

Uterine biology in pigs and sheep

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.

PREFACE

Reproduction is essential for the health and well-being of humans, livestock, companion animals, and wildlife populations. Regarding animal agriculture, reproductive efficiency is a major limitation in many cases to economic success of the livestock enterprise. This is due to high rates of embryonic mortality and intra-uterine growth restriction that reduce reproductive efficiency and production of health offspring in humans and animals.