Hemochorial placentation is utilized in many mammalian species including rodents and primates. It ensures the most intimate contacts between maternal and embryonic compartments. Among these changes is the extensive remodeling of the associated maternal uterine vasculature. The uterine vascular modifications are fundamental to the delivery of nutrients to the developing embryo/fetus. Mechanisms underlying the control of uteroplacental vascular remodeling are not well understood. A key regulator of pregnancy-dependent changes in the uterine vasculature is a specialized lineage of trophoblast cells referred to as invasive trophoblast. The vascular modifications initiated by invasive trophoblast are fundamental to ensuring adequate nutrient flow to the fetus. We have identified two model systems to investigate mechanisms controlling the invasive trophoblast lineage. One is environmentally activated by hypoxia and the second is genetic, taking advantage of the Brown Norway (BN) inbred rat and BN consomic rat strains. Maternal hypoxia during critical phases of placentation can activate the invasive trophoblast lineage, resulting in premature and robust migration of invasive trophoblast cells, extending well into the uterine mesometrial vasculature. The BN inbred rat has restricted trophoblast cell invasion and has been used to generate consomic rat strains with the Dahl SS (DSS) rat, the latter possessing robust trophoblast cell invasion. We will also use reporter transgenes to specifically tag and monitor the behavior of the invasive trophoblast cell lineage. Thus we will utilize novel strategies for elucidating mechanisms controlling the invasive trophoblast lineage. Two major specific aims are proposed.
In Aim No. 1, we will examine the effects of maternal hypoxia on development of the invasive trophoblast lineage. The focus of Aim No. 2 is on investigating mechanisms underlying BN rat trophoblast cell invasion defects. We assert that intrauterine trophoblast cell invasion is a critical first step in the regulation of pregnancy-dependent uteroplacental vascular adaptations, which are essential for embryonic/fetal nutrient delivery. Furthermore we propose that these adaptive mechanisms are the sites of disruption in diseases of pregnancy, such as preeclampsia and intrauterine growth restriction. In this research project, we outline experiments designed to evaluate mechanisms controlling the invasive trophoblast lineage. ? ? ?
| Soares, Michael J; Varberg, Kaela M; Iqbal, Khursheed (2018) Hemochorial placentation: development, function, and adaptations. Biol Reprod 99:196-211 |
| Bu, Pengli; Yagi, Shintaro; Shiota, Kunio et al. (2017) Origin of a rapidly evolving homeostatic control system programming testis function. J Endocrinol 234:217-232 |
| Chakraborty, Damayanti; Muto, Masanaga; Soares, Michael J (2017) Ex vivo Trophoblast-specific Genetic Manipulation Using Lentiviral Delivery. Bio Protoc 7: |
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| Dhakal, Pramod; Soares, Michael J (2017) Single-step PCR-based genetic sex determination of rat tissues and cells. Biotechniques 62:232-233 |
| Soares, Michael J; Iqbal, Khursheed; Kozai, Keisuke (2017) Hypoxia and Placental Development. Birth Defects Res 109:1309-1329 |
| Renaud, Stephen J; Scott, Regan L; Chakraborty, Damayanti et al. (2017) Natural killer-cell deficiency alters placental development in rats. Biol Reprod 96:145-158 |
| Soares, Michael J; Vivian, Jay L (2016) Tipping the balance toward trophoblast development. Proc Natl Acad Sci U S A 113:5144-6 |
| Bu, Pengli; Alam, Sheikh M Khorshed; Dhakal, Pramod et al. (2016) A Prolactin Family Paralog Regulates Placental Adaptations to a Physiological Stressor. Biol Reprod 94:107 |
| Imakawa, Kazuhiko; Dhakal, Pramod; Kubota, Kaiyu et al. (2016) CITED2 modulation of trophoblast cell differentiation: insights from global transcriptome analysis. Reproduction 151:509-16 |
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