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）：这是对研究项目的接下来五年的竞争续签申请，其长期目标是确定怀孕和子痫前期高血压的血管和细胞机制。初步工作表明，孕妇大鼠的子宫酸性灌注压力（RUPP）局部降低与全身性血管收缩和高血压有关。但是，连接局部RUPP和广义血管收缩的分子机制尚不清楚。该提案的总体目的是检验指导假设：TNF-A，IL-6或IL-1B等母体血浆细胞因子的升高是将妊娠期间局部RUPP与普遍性血管收缩和高血压联系起来的局部RUPP的关键中介机制。具体而言，研究旨在测试：1）怀孕期间的RUPP与循环细胞因子的上调有关； 2）母体血浆细胞因子的升高与抑制内皮依赖性一氧化氮（NO）-CGMP，Prostacyclin（PGI2）-CAMP和/或超极化因子松弛途径（EDHF）有关； 3）血浆细胞因子的升高与增强的血管平滑肌（VSM）收缩机制相关，即[Ca2+] I和特定PKC同工型的表达/活性； 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； 5）血浆细胞因子的下调可防止妊娠期间与RUPP相关的BP和血管功能障碍的增加。为了解决这些目的，持续爆发的Rupp大鼠，并用TNF-A，IL-6或IL-1B长期注入孕妇的大鼠，以模拟先兆子痫的女性中观察到的血浆水平。一种独特的整合方法将在整个动物，血管，细胞和分子水平上利用一系列相互关联的机械研究来研究怀孕期间细胞因子水平之间可能的因果关系，细胞因子诱导的肾脏放松机制的变化在肾脏和Mesenteric Microvessel和Mesenteric Microvessels and Brivencess and trivences and trivences and trivens and bect and bpp and bpp bect bpp bpp bpp bpp bpp bpp inthereperation的机制中的变化。这些研究应有助于更好地理解细胞因子作为在怀孕和高血压期间将RUPP联系起来的中介机制，并阐明了怀孕和先兆子痫高血压的病理生理血管机制。