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

• 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
• 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

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.

项目摘要 我们实验室的工作发现， 在成年期产生高血压反应的持续敏感性， 挑战我们最近的研究表明，具有血管紧张素II的母鼠的成年雄性后代， 妊娠期高血压或在围产期吃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， 脑血管紧张素-醛固酮系统的组成部分，促炎细胞因子和激活 控制交感神经张力和血压的前脑结构中的小胶质细胞。重要的是，我们发现， 在断奶和早期断奶之间向致敏的后代施用转化酶抑制剂六周， 成年消除了妊娠期高血压引起的高血压反应的敏感性。本 建议建立在这些发现的实验，将确定：1）关键的围产期时， 高血压反应可由母体妊娠高血压致敏，2）如果母体妊娠高血压 高血压改变母子行为，诱导高血压反应敏感化，3）是否 小神经胶质细胞活化的抑制剂和促炎细胞因子以及其它的肾素-血管紧张素-血管紧张素受体阻滞剂， 醛固酮系统将逆转母体妊娠高血压和母体妊娠高血压的增敏作用。 围产期高脂肪饮食摄入，4）为什么年轻女性免受高血压反应致敏， 5)如果母体妊娠期高血压或高脂肪饮食摄入诱导了对识别的 高血压的危险因素与饮食性肥胖、钠摄入量以及哪些因素负责维持 敏感的反应这一信息将通过使用遥测技术测量自由血压来获得 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细胞中mRNA和蛋白质表达的变化， 控制血压的中枢神经系统关键区域。完成拟议的实验将导致交付 关于胎儿编程如何导致增加表达的可能性的重要新信息， 增强的高血压在以后的生活和措施，可以用来预防它。