This is a competing renewal application for funding of the next five years of a research project whose long- term goal is the determination of the vascular and cellular mechanisms of hypertension in pregnancy and preeclampsia. Preliminary work suggests that localized reduction in uteroplacental perfusion pressure (RUPP) in pregnant rats is associated with systemic vasoconstriction and hypertension. However, the molecular mechanisms linking localized RUPP and the generalized vasoconstriction are unclear. The overall objective of this proposal is to test the guiding hypothesis that elevation of the level of maternal plasma cytokines such as TNF-a, IL-6 or IL-1b is a pivotal intermediary mechanism linking localized RUPP during pregnancy to the generalized vasoconstriction and hypertension. Specifically, studies are designed to test whether: 1) RUPP during pregnancy is associated with upregulation of circulating cytokines;2) elevation of maternal plasma cytokines is associated with inhibition of endothelium-dependent nitric oxide (NO)-cGMP, prostacyclin (PGI2)-cAMP, and/or hyperpolarizing factor relaxation pathway (EDHF);3) elevation of plasma cytokines is associated with enhanced mechanisms of vascular smooth muscle (VSM) contraction namely [Ca2+]i and the expression/activity of specific PKC isoforms;4) the cytokines-induced changes in vascular function involve direct effects on the endothelium and VSM;and 5) downregulation of plasma cytokines prevents the increases in BP and vascular dysfunction associated with RUPP during pregnancy. To address these aims chronically-instrumented RUPP rats, and pregnant rats chronically-infused with TNF-a, IL-6 or IL- 1b to mimic the plasma levels observed in women with preeclampsia will be used. A unique integrative approach will utilize an array of interrelated mechanistic studies at the whole animal, vascular, cell and molecular level to investigate a possible causal relation between the levels of cytokines during pregnancy, the cytokine-induced alterations in the mechanisms of endothelial relaxation and VSM contraction in renal and mesenteric microvessels, and the increased BP observed during hypertension in pregnancy. These studies should help to understand better the role of cytokines as an intermediary mechanism linking RUPP during pregnancy and hypertension, and shed light on the pathophysiological vascular mechanisms of hypertension in pregnancy and preeclampsia.
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