Hemochorial placentation is utilized in many mammalian species including rodents and primates. It ensures the most intimate contacts between maternal and embryonic compartments. This type of placentation presents apparent advantages but also considerable challenges to the well being of mother and fetus. Specialized adaptations occur within the female reproductive tract to accommodate the needs of the developing embryo and fetus. Among these changes are the differentiation of uterine stromal cells into decidua and the extensive development of the associated maternal uterine vasculature. The uterine vascular modifications are fundamental to the delivery of nutrients to the developing fetus. Mechanisms underlying the control of uteroplacental vascular remodeling are not well understood. The key regulators of the pregnancy-dependent changes in the vasculature are natural killer (NK) cells during early pregnancy and trophoblast cells during the latter stages of pregnancy. We have identified a reproducible in vivo method impacting the development of the uteroplacental vasculature. Exposure of pregnant rodents to hypobaric-hypoxia results in a profound remodeling of uteroplacental blood vessels. This effect on the maternal uterine vasculature is dramatic and largely protects the fetus from intrauterine growth restriction. We hypothesize that the hypobaric-hypoxia challenge results in an exaggeration of normal pregnancy-dependent uteroplacental vascular adjustments. Furthermore we propose that failures in these maternal-fetal adaptations result in pathologies in the mother and/or fetus. In this proposal, we outline experiments designed to evaluate cellular and molecular mechanisms underlying the maternal compensatory response to maternal hypobaric-hypoxia, including the regulatory roles of NK cells and the trophoblast-specific cytokine, prolactin-like protein-A (PLP-A). We have presented novel ideas and a novel research approach to elucidate regulatory mechanisms controlling fundamental processes essential for the establishment and maintenance of pregnancy. ? ?

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Ilekis, John V
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University of Kansas
Schools of Medicine
Kansas City
United States
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Chakraborty, Damayanti; Rumi, M A Karim; Soares, Michael J (2012) NK cells, hypoxia and trophoblast cell differentiation. Cell Cycle 11:2427-30
Renaud, S J; Karim Rumi, M A; Soares, M J (2011) Review: Genetic manipulation of the rodent placenta. Placenta 32 Suppl 2:S130-5
Dai, Guoli; Bustamante, Juan J; Zou, Yuhong et al. (2011) Maternal hepatic growth response to pregnancy in the mouse. Exp Biol Med (Maywood) 236:1322-32
Asanoma, Kazuo; Rumi, M A Karim; Kent, Lindsey N et al. (2011) FGF4-dependent stem cells derived from rat blastocysts differentiate along the trophoblast lineage. Dev Biol 351:110-9
Chakraborty, Damayanti; Rumi, M A Karim; Konno, Toshihiro et al. (2011) Natural killer cells direct hemochorial placentation by regulating hypoxia-inducible factor dependent trophoblast lineage decisions. Proc Natl Acad Sci U S A 108:16295-300
Konno, Toshihiro; Graham, Amanda R; Rempel, Lea A et al. (2010) Subfertility linked to combined luteal insufficiency and uterine progesterone resistance. Endocrinology 151:4537-50
Alam, S M Khorshed; Konno, Toshihiro; Rumi, M A Karim et al. (2010) Prolactin family of the guinea pig, Cavia porcellus. Endocrinology 151:3918-28
Bustamante, Juan J; Copple, Bryan L; Soares, Michael J et al. (2010) Gene profiling of maternal hepatic adaptations to pregnancy. Liver Int 30:406-15
Kent, Lindsey N; Konno, Toshihiro; Soares, Michael J (2010) Phosphatidylinositol 3 kinase modulation of trophoblast cell differentiation. BMC Dev Biol 10:97
Rosario, G X; Ain, R; Konno, T et al. (2009) Intrauterine fate of invasive trophoblast cells. Placenta 30:457-63

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