The placenta and uterus conduct an essential dialogue at the maternal- fetal interface for the initiation, maintenance and completion of pregnancy via the coordinated functions of trophoblasts in contact with maternal blood, and the fetal vasculature within the chorionic in the placental vascular system in diabetic pregnancies is incompletely understood. Our overall hypothesis is that the dysregulation of glucose disposition in Type I diabetic pregnancy precipitates changes in angiogenesis impacting the placental villous vasculature, responsible for the pathophysiology of fetal growth and maternal well-being associated with the Type I diabetic pregnancy. We further hypothesize that glucose and oxygen-mediated pathways influence placental (trophoblast) regulation of angiogenesis. In order to test these hypotheses, we have set the following Specific Aims.
Specific Aim 1, To define the changes in expression of mRNAs and proteins important for angiogenic and vasodilatory adaptation in normal and Type I diabetic placentas. Expt.1A/B. Angiogenic factors, eNOS, oxidative stress marker expression in viii and placental vessels Expt. 1C Morphometric analysis of placental villous proliferation, structure and vascular density. Expt. 1D Molecular phenotyping of the diabetic placenta Specific Aim 2. Define in vitro the mechanisms by which glucose, NO and hypoxia alter placental angiogenesis. Expt 2B. Effects of diabetes on trophoblast function and glucose-oxygen responsiveness Expt. 2D Evaluate the role of eNOS/NO in mediating glucose effects on trophoblast function Expt. 2D Evaluate the role of oxidative stress in glucose effects on trophoblast function. Reductions in placental vascularity due to the disruption of angiogenesis in Type 1 diabetic pregnancy can lead to decreased placental blood flow and reduction in fetal weight, survivability and health of the neonate. The mother is also at increased risk for development of ketoacidosis, pyelonephritis and preeclampsia. Type I Diabetes during pregnancy may have additional significance in the offspring for the long-term health and risk for adult disease. A better understanding of the intrauterine environment and its regulation will benefit not only maternal and fetal health, but also further the understanding of disease processes in all individuals.
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