Vascular Mechanisms in Pregnancy-Induced Hypertension

描述(由申请人提供)：这是一个研究项目未来五年的竞争性续签申请，其长期目标是确定妊娠期高血压和先兆子痫的血管和细胞机制。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，连接局部RUPP和全身性血管收缩的分子机制尚不清楚。这项建议的总体目标是检验指导性假说，即母体血浆细胞因子水平的升高是将妊娠期局限性RUPP与全身性血管收缩和高血压联系起来的关键中介机制。具体地说，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)孕妇血浆细胞因子升高与内皮依赖的一氧化氮(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)收缩的增强机制有关，即[Ca~(2+)]i和特定的PKC亚型的表达/活性；4)细胞因子诱导的血管功能变化直接影响内皮和VSM；5)下调血浆细胞因子水平可预防妊娠期RUPP引起的血压升高和血管功能障碍。为了达到这些目的，将使用长期仪器化的RUPP大鼠和长期注入TNF-a、IL-6或IL-1b的怀孕大鼠，以模拟观察到的先兆子痫妇女的血浆水平。一种独特的综合方法将利用整个动物、血管、细胞和分子水平上的一系列相互关联的机制研究，以探讨妊娠期细胞因子水平、细胞因子诱导的肾和肠系膜微血管内皮细胞松弛和VSM收缩机制的变化与妊娠期高血压期间血压升高之间的可能因果关系。这些研究将有助于更好地了解细胞因子在妊娠期RUPP和高血压之间的中介机制的作用，并有助于阐明妊娠期高血压和先兆子痫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.