Diabetes mellitus is one of the most common medical complications of pregnancy that significantly contributes to maternal and perinatal morbidity and mortality. Women with pregnancies complicated by diabetes are also at a higher risk for the development of hypertension and preeclampsia. A decreased uteroplacental blood flow in diabetic pregnancy suggests an abnormal uterine artery structural or/and functional adaptation causing placental and fetal hypoxia and increased rates of hypertension in pregnancy and preeclampsia. The long-term goal of this proposal is to understand the causes and cellular and molecular mechanisms underlying uteroplacental endothelial dysfunction induced by diabetic pregnancy, with a specific focus on the role of hyperglycemia, PKC and peroxisome proliferator-activated receptor gamma (PPARg) in this process. Our central hypothesis is that diabetes in pregnancy causes endothelial dysfunction of uteroplacental arteries manifested by decreased NO- and EDHF-mediated vasodilation. Hyperglycemia-induced PKC activation results in impairment of Ca2+ signaling leading to decreased production of NO and diminished stimulation of Ca2+-activated potassium channels (SKCa and IKCa) (Specific Aim 1). PKC-specific inhibition of SKCa and IKCa channels is an additional novel mechanism of impaired EDHF-mediated vasodilation in diabetes (Specific Aim 2). Hyperglycemia-induced superoxide production up-regulates PDE expression resulting in reduction of NO- cGMP-PKG signaling and development of nitric oxide resistance in diabetic pregnancy (Specific Aim 3). Direct beneficial effects of PPARg on arterial function in diabetic pregnancy results from moderation in DAG-PKC activity and is mediated by inhibition of superoxide production and up-regulation of DAG-kinase. Furthermore, we propose that hyperglycemia-PKC down-regulates PPARg expression contributing to diabetes-induced impairment of cellular and molecular mechanisms responsible for maternal uterine adaptation in pregnancy (Specific Aim 4). We propose to use a rat model of STZ-induced diabetes to explore the effects of hyperglycemia in uteroplacental vascular dysfunction in pregnancy. We will focus on a specific part of the maternal uterine vasculature - small radial uterine arteries - that regulate the blood supply to the placenta and fetus. The four Specific aims will integrate physiological function (regulation of arterial diameter) with intracellular mechanisms (Ca2+ signaling and ion channel function) and will be accomplished by direct measurements of arterial diameter, intracellular Ca2+ and NO, membrane potential, expression and distribution of PKC and PDE, and ion currents in single endothelial and smooth muscle cells.
The proposed studies will provide new insights into the role of hyperglycemia, PKC and PPARg in diabetes- induced modulation of intracellular molecular mechanisms regulating uteroplacental vascular function and significantly improve our knowledge of the mechanisms underlying abnormal maternal uterine circulation in pregnancies complicated by diabetes.
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