Mechanisms of hypertensive response sensitization and perinatal programming of hypertension

高血压反应敏化机制和围产期高血压规划

基本信息

批准号：
9593048
负责人：
ALAN Kim JOHNSON
金额：
$ 57.16万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9593048
关键词：
Address Adult Angiotensin II Angiotensins Behavior Behavioral Biological Neural Networks Blood Pressure Brain Cytokine Activation Diet Dietary Factors Disease Eating Enzyme Inhibitor Drugs Etiology Exposure to Female Fetus High Fat Diet Hypertension Inflammation Inflammation Mediators Inflammatory Intake Intervention Knowledge Laboratories Learning Life Literature Measures Mediating Mediator of activation protein Memory Methods Microglia Modeling Molecular Mothers Nervous system structure Neuraxis Neuronal Plasticity Obesity Pathogenesis Perinatal Pharmacology Physiological Pregnant Women Process Prosencephalon Rattus Renin-Angiotensin-Aldosterone System Risk Factors Role Signal Transduction Sodium Sodium Chloride Stimulus Stress Structure Sympathetic Nervous System Telemetry Testing Time Weaning Work behavioral response blood pressure regulation brain pathway critical period cytokine emerging adult experience experimental study fetal fetal programming in utero inhibitor/antagonist innovation mRNA Expression male mature animal neonate novel novel therapeutic intervention offspring perinatal period pregnancy hypertension prevent programs protein expression response stressor young adult

项目摘要

PROJECT SUMMARY Work from our laboratory discovered that mild physiological and environmental challenges encountered earlier in adulthood produce sustained sensitization of the hypertensive response to subsequent hypertensinogenic challenges. Our recent studies indicate that the adult male offspring of dams with angiotensin II-produced gestational hypertension or eating a high-fat diet during the perinatal period also display sensitization of the hypertensive response. Accompanying this exacerbation of the hypertensive response is increased expression of components of the brain renin-angiotensin-aldosterone system, proinflammatory cytokines and activation of microglia in forebrain structures controlling sympathetic tone and blood pressure. Importantly, we find that administering a converting enzyme inhibitor to the sensitized offspring for six weeks between weaning and early adulthood abrogates gestational hypertension-induced sensitization of the hypertensive response. The present proposal builds on these findings with experiments that will determine: 1) the critical perinatal period when the hypertensive response can be sensitized by maternal gestational hypertension, 2) if maternal gestational hypertension alters mother-offspring behaviors to induce hypertensive response sensitization, 3) whether inhibitors of microglial activation and proinflammatory cytokines and other blockers of the renin-angiotensin- aldosterone system will reverse the sensitizing effects of maternal gestational hypertension and maternal perinatal high-fat diet intake, 4) why young females are protected against hypertensive response sensitization, 5) if maternal gestational hypertension or high-fat diet intake induces sensitized responses to identified hypertension risk factors related to dietary obesity, sodium intake and what factors are responsible of maintaining a sensitized response. This information will be obtained by using telemetry to measure blood pressure in freely moving rats and pharmacological methods to test mechanisms mediating hypertensive response sensitization. In addition molecular expression methods be used to characterize changes in mRNA and protein expression in key CNS regions controlling blood pressure. Completion of the proposed experiments will result in the delivery of important new information on how fetal programming results in increasing the likelihood of expression of enhanced hypertension later in life and measures that can be used to prevent it.

项目概要我们实验室的工作发现，早期遇到的轻微生理和环境挑战在成年期对随后的高血压产生持续的高血压反应敏化挑战。我们最近的研究表明，血管紧张素 II 产生的成年雄性后代妊娠期高血压或围产期食用高脂肪饮食也显示出对高血压反应。伴随着高血压反应的加剧的是表达的增加脑肾素-血管紧张素-醛固酮系统的组成部分、促炎细胞因子和激活前脑结构中的小胶质细胞控制交感神经张力和血压。重要的是，我们发现在断奶和早期之间对致敏后代施用转换酶抑制剂六周成年期消除了妊娠期高血压引起的高血压反应的敏化。现在的该提案建立在这些发现的基础上，通过实验确定：1）关键的围产期母亲妊娠期高血压可导致高血压反应敏感，2) 如果母亲妊娠期高血压高血压改变母子行为以诱发高血压反应敏化，3）是否小胶质细胞激活和促炎细胞因子的抑制剂以及肾素-血管紧张素-的其他阻断剂醛固酮系统将逆转母亲妊娠期高血压和母亲的致敏作用围产期高脂肪饮食摄入量，4) 为什么年轻女性可以免受高血压反应敏化， 5) 如果母亲妊娠期高血压或高脂肪饮食摄入引起对已确定的过敏反应高血压危险因素与饮食肥胖、钠摄入量以及哪些因素负责维持敏感的反应。该信息将通过使用遥测技术自由测量血压来获得移动大鼠和药理学方法来测试介导高血压反应致敏的机制。此外，分子表达方法可用于表征 mRNA 和蛋白质表达的变化控制血压的关键中枢神经系统区域。完成拟议的实验将导致交付关于胎儿编程如何增加表达可能性的重要新信息晚年高血压的发生率以及可用于预防高血压的措施。