Regulation of Pregnancy-Dependent Adaptations

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DESCRIPTION (provided by applicant): 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 research project, 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-derived cytokine, prolactin-like protein-A (PLP-A). The experimentation utilizes genetically manipulated mutant mouse strains deficient in NK cells, interferon-y, and PLP-A. Novel ideas and a novel research approach have been presented to elucidate regulatory mechanisms controlling fundamental processes essential for the establishment and maintenance of pregnancy.