Vascular Mechanisms in Pregnancy-Induced Hypertension

描述（由申请人提供）：这是一份为未来五年的研究项目提供资金的竞争性更新申请，该研究项目的长期目标是确定妊娠期高血压和子痫前期的血管和细胞机制。初步研究表明，妊娠大鼠子宫胎盘灌注压（RUPP）的局部降低与全身血管收缩和高血压有关。然而，局部RUPP与全身性血管收缩的分子机制尚不清楚。本研究的总体目标是验证母体血浆细胞因子（如TNF-a、IL-6或IL-1b）水平的升高是将妊娠期局部RUPP与全身性血管收缩和高血压联系起来的关键中介机制。具体而言，研究旨在检验：1)妊娠期RUPP是否与循环细胞因子上调有关；2)母体血浆细胞因子的升高与内皮依赖性一氧化氮(NO)-cGMP、前列环素(PGI2)-cAMP和/或超极化因子松弛途径（EDHF）的抑制有关；3)血浆细胞因子的升高与血管平滑肌（VSM）收缩机制的增强有关，即[Ca2+]i和特定PKC亚型的表达/活性；4)细胞因子诱导的血管功能改变涉及对内皮和VSM的直接影响；5)血浆细胞因子下调可防止妊娠期RUPP相关的血压升高和血管功能障碍。为了实现这些目标，将使用长期监测的RUPP大鼠和妊娠大鼠长期注射TNF-a、IL-6或IL- 1b来模拟子痫前期妇女的血浆水平。一种独特的综合方法将在全动物、血管、细胞和分子水平上利用一系列相互关联的机制研究来研究妊娠期间细胞因子水平、细胞因子诱导的肾脏和肠系膜微血管内皮松弛和VSM收缩机制的改变以及妊娠高血压期间观察到的血压升高之间可能的因果关系。这些研究将有助于更好地了解细胞因子作为妊娠期RUPP与高血压之间的中介机制，并揭示妊娠期高血压和子痫前期的病理生理血管机制。

DESCRIPTION (provided by applicant): 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.