Pregnancy Shifts ACE2/ACE Balance to Ang-(1-7)

怀孕使 ACE2/ACE 平衡转变为 Ang-(1-7)

• 批准号: 7386018
• 负责人: Kathleen Bridget Brosnihan
• 金额: $ 26.33万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386018
• 关键词: 129 Mouse; Affinity; Angiopoietin-2; Angiotensin-Converting Enzyme Inhibitors; Angiotensin-converting Enzyme 2 Pathway; Animal Model; Antihypertensive Agents; Arteries; Beds; Binding; Biochemical; Blood Circulation; Blood Pressure; Blood Vessels; Carboxypeptidase; Cardiac Output; Cardiovascular system; Catalytic Domain; Chromosome Mapping; Chronic; Condition; Data; Decidua; Detection; Dilator; Dimensions; Elevation; Enzymes; Equilibrium; Evolution; Excretory function; Exhibits; GTP-Binding Proteins; Genes; High Blood Pressure; Homologous Gene; Human; Hypertension; Hypertension induced by pregnancy; Ischemia; Kidney; Kinins; Knockout Mice; Laboratories; Lead; Localized; Menstrual cycle; Mesentery; Metabolism; Modeling; Molecular; Mus; Numbers; Pathology; Pathway interactions; Patient currently pregnant; Peptidyl-Dipeptidase A; Perfusion; Peripheral Resistance; Physiological; Physiology; Placenta; Plasma; Pre-Eclampsia; Pregnancy; Pregnant Uterus; Pregnant Women; Prostaglandins; Protein Overexpression; Quantitative Trait Loci; Rate; Rattus; Regulation; Relative (related person); Renin-Angiotensin System; Reporting; Research; Resistance; Role; System; Testing; Tissues; Transcriptional Activation; Up-Regulation; Upper arm; Urine; Uterus; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; angiotensin I (1-7); arteriole; base; blood pressure regulation; fetal; hemodynamics; implantation; inhibitor/antagonist; insight; novel; pregnancy disorder; pregnancy hypertension; pressure; receptor; response; size; tool; trophoblast; urinary; vascular bed

Our group first showed that angiotensin-(1-7) [Ang-(1-7)] increases in the plasma and urine of normal pregnant women. In preeclamptic pregnant subjects we demonstrated a decrease of plasma Ang-(1-7) greater than that of Ang II. These initial findings provide a basis for an important physiological role for Ang-(1-7) in the course of pregnancy and in pregnancy-induced hypertension (PIH) where there may be a diminished influence of Ang-(1-7) to oppose the local tissue actions of Ang II. New data from our laboratory showed that Ang-(1-7) enhanced mesentery artery dilation in pregnancy and this was accompanied by increased kidney and urine levels of Ang-(1-7) in normal pregnant rats. Preliminary studies showed that urinary excretion of Ang-(1-7) was reduced in an animal model that resembles PIH. In addition, our recent discovery that angiotensin converting enzyme 2 (ACE2), a carboxypeptidase that exhibits high efficacy for Ang II metabolism to Ang-(1-7), is present in the kidney and uterus of pregnant rats, is localized to similar regions in kidney and uterus as Ang-(1-7), and is up-regulated in pregnancy suggests the hypothesis that increased expression of ACE2 leads to an enhanced formation of Ang-(1-7) during pregnancy. The hypothesis to be assessed in these studies is twofold: 1) that pregnancy is a model of overexpression of Ang-(1-7) resulting from increased expression of ACE2; 2) that the resulting hemodynamic profile (i.e the decreased peripheral resistance seen in normal pregnancy) is dependent upon up-regulation of ACE2 leading to enhanced formation of Ang-(1-7), whereas PIH (characterized by increased total peripheral resistance and uteroplacental ischemia) is due to unbridled pressor/ischemic actions of Ang-II as a consequence of a marked reduction of the formation and vasodepressor effects of Ang-(1-7). The Specific Aims are: 1) to assess the evolutionary expression of Ang-(1-7) and ACE2 at early, mid and late gestation in normal and the reduced uterine perfusion pressure (RUPP) pregnant rats; 2) to determine the contribution of the ACE2 pathway to Ang-(1-7) formation at early, mid and late gestation in normal pregnant and RUPP pregnant rats; 3) to assess the systemic and regional hemodynamic role of Ang-(1-7) and ACE2 in normal and RUPP pregnant rats; and 4) to characterize the null ACE2-/- pregnant mouse by detertm'ning the impact of the loss of the gene on blood pressure regulation. The proposed research will establish a novel and significant new dimension to the contribution of the RAS in the physiology and pathology of pregnancy.

本研究组首次发现正常孕妇血浆和尿液中血管紧张素-（1 - 7）[Ang-（1 - 7）]升高。在先兆子痫妊娠受试者中，我们证明血浆Ang-（1 - 7）的降低大于Ang II。这些初步发现为Ang-（1 - 7）在妊娠过程中和妊娠高血压（PIH）中的重要生理作用提供了基础，其中可能存在Ang-（1 - 7）对抗Ang II的局部组织作用的减弱的影响。我们实验室的新数据表明，Ang-（1 - 7）增强妊娠期肠系膜动脉扩张，并伴随肾脏和尿液增加 正常妊娠大鼠血管紧张素-（1 - 7）水平。初步研究表明，在类似PIH的动物模型中，Ang-（1 - 7）的尿排泄减少。此外，我们最近发现，血管紧张素转化酶2（ACE2），一种对Ang II代谢为Ang-（1 - 7）表现出高效力的羧肽酶，存在于妊娠大鼠的肾脏和子宫中，定位于肾脏和子宫中与Ang-（1 - 7）相似的区域，并且在妊娠中上调提示了这样的假设，即在妊娠期间ACE 2的表达增加导致Ang-（1 - 7）的形成增强。这些研究中要评估的假设是双重的：1）妊娠是ACE 2表达增加导致的Ang-（1 - 7）过表达的模型; 2）所产生的血液动力学特征（即在正常妊娠中观察到的外周阻力降低）依赖于ACE 2的上调，导致Ang-（1 - 7）的形成增强，而妊高征（特征为总外周阻力增加和子宫胎盘缺血）是由于Ang-（1 - 7）的形成和血管抑制作用显著减少导致Ang-II的无节制的升压/缺血作用。具体目标是：1）评估Ang-（1 - 7）和ACE 2在正常和子宫灌注压降低（RUPP）妊娠大鼠中在妊娠早期、中期和晚期的进化表达; 2）确定ACE 2通路对早期Ang-（1 - 7）形成的贡献， 在正常妊娠和RUPP妊娠大鼠中的妊娠中期和晚期; 3）评估Ang-（1 - 7）和ACE 2在正常和RUPP妊娠大鼠中的全身和局部血液动力学作用;和4）通过测定基因缺失对血压调节的影响来表征无效ACE 2-/-妊娠小鼠。这项研究将为RAS在妊娠生理学和病理学中的贡献建立一个新的、重要的新维度。