Vascular Mechanisms in Pregnancy-Induced Hypertension

妊娠高血压综合征的血管机制

• 批准号: 7822236
• 负责人: Raouf A Khalil
• 金额: $ 2.4万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7822236
• 关键词: Address; Affect; Animals; Biochemical; Biological Assay; Blood Pressure; Blood Vessels; Characteristics; Confocal Microscopy; Cyclic AMP; Cyclic GMP; Disease; Down-Regulation; Endothelium; Enzyme-Linked Immunosorbent Assay; Enzymes; Functional disorder; Funding; Fura-2; Goals; Hypertension; Hypertension induced by pregnancy; Immunoblotting; Immunofluorescence Immunologic; Interleukin-6; Ischemia; Kidney; Light; Link; Lymphocyte; Measures; Mediating; Mesenteric Arteries; Mesentery; Messenger RNA; Microscopy; Modeling; Molecular; Morbidity - disease rate; Muscle Contraction; Nitric Oxide; Particulate; Pathway interactions; Perfusion; Peripheral Resistance; Physiological; Placenta; Plasma; Pre-Eclampsia; Pregnancy; Pregnant Women; Prostaglandins I; Protein Isoforms; Proteinuria; Radioimmunoassay; Rattus; Relaxation; Renal Blood Flow; Research; Research Design; Research Personnel; Research Project Grants; Reverse Transcriptase Polymerase Chain Reaction; Role; Smooth Muscle; Smooth Muscle Myocytes; Testing; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Up-Regulation; Vascular Endothelium; Vascular Endothelium-Dependent Relaxation; Vascular Smooth Muscle; Vascular resistance; Woman; Work; cytokine; digital imaging; fetal; instrument; mortality; pregnancy hypertension; pregnant; pressure; prevent; programs; vasoconstriction

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.

描述（由申请人提供）：这是一个竞争性的更新申请，用于资助一个研究项目的未来五年，该项目的长期目标是确定妊娠高血压和先兆子痫的血管和细胞机制。初步工作表明，在妊娠大鼠子宫胎盘灌注压（RUPP）的局部减少与全身血管收缩和高血压。然而，局部RUPP和全身血管收缩的分子机制尚不清楚。该建议的总体目标是检验以下指导性假设：母体血浆细胞因子如TNF-α、IL-6或IL-1b水平的升高是将妊娠期间局部RUPP与全身血管收缩和高血压联系起来的关键中介机制。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（PGI 2）-cAMP和/或超极化因子松弛途径（EDHF）的抑制有关;（3）血浆细胞因子水平升高与血管平滑肌收缩机制（[Ca ~（2+）]i）增强和PKC特异性亚型的表达/活性增强有关; 4）细胞因子诱导的血管功能变化涉及对内皮和VSM的直接影响;和5）血浆细胞因子的下调防止妊娠期间与RUPP相关的BP增加和血管功能障碍。为了解决这些目的，将使用长期仪器化的RUPP大鼠和长期输注TNF-α、IL-6或IL- 1b以模拟在患有先兆子痫的女性中观察到的血浆水平的妊娠大鼠。一种独特的综合方法将利用一系列在整个动物、血管、细胞和分子水平上相互关联的机制研究来研究妊娠期间细胞因子水平、细胞因子诱导的肾和肠系膜微血管内皮舒张和VSM收缩机制的改变之间可能的因果关系。血管，以及妊娠高血压期间观察到的血压升高。这些研究将有助于更好地理解细胞因子作为妊娠期RUPP和高血压之间的中介机制的作用，并阐明妊娠期高血压和先兆子痫的病理生理血管机制。