Early Life Stress & Chronic Control of Blood Pressure

早期生活压力

• 批准号: 8734478
• 负责人: Analia Loria
• 金额: $ 24.4万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-23 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734478
• 关键词: Acute; Adipose tissue; Adrenergic Agents; Adult; Aldosterone; Angiotensin II; Attenuated; Behavioral; Biochemical; Biological; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Caring; Child; Childhood; Chronic; Corticosterone; Data; Development; Diabetes Mellitus; Diet; Disease; Drops; Environment; Epidemic; Event; Excretory function; Exposure to; Fatty acid glycerol esters; Filtration; Functional disorder; Ganglia; Glomerular Filtration Rate; Health Care Costs; Human; Hypertension; Infusion procedures; Investigation; Kidney; Kidney Diseases; Leptin; Life; Life Stress; Life Style; Maintenance; Mediating; Mentors; Minor; Modeling; Molecular; Mothers; Nerve; Obesity; Organ; Outcome; Pathway interactions; Pediatrics; Perinatal; Phase; Phenylephrine; Physiological; Plasma; Predisposition; Proteins; Public Health; Rattus; Receptor Activation; Receptor, Angiotensin, Type 1; Renal Tissue; Renal function; Renin; Renin-Angiotensin-Aldosterone System; Reporting; Research; Risk Factors; Rodent; Secondary to; Stress; System; Techniques; Testing; Therapeutic; Variant; adrenergic; blood pressure regulation; desensitization; in vivo; maternal separation; novel; premature; pressure; programs; pup; receptor expression; response; stressor; vasoconstriction

PROJECT SUMMARY Chronic adult diseases, such as hypertension, diabetes or obesity, may develop as a consequence of early life stress (ELS). Adverse childhood events are highly correlated with enhanced cardiovascular response to a secondary stressor, a "second hit". Maternal separation is an established model of chronic behavioral stress in rodents that involves separating pups from their mothers 3 hr/day from days 2-14 of life. Adult maternally separated (MS) rats show lower glomerular filtration rate under baseline conditions compared to control, un-separated littermates, with no difference in blood pressure. Interestingly, the phenylephrine-induced vasoconstriction in the kidney is attenuated but the drop in blood pressure elicited by ganglion blockade is greater in MS rats. These data suggest increased sympathetic activation in MS rats. In contrast, the acute pressor response to angiotensin II (AngII) is comparable between MS and control rats whereas MS rats show exaggerated chronic AngII-induced hypertension. Thus, our data suggest that ELS impairs the ability of the kidney to control blood pressure following a "second hit". Taken together, we hypothesize that rats exposed to MS display increased renal sympathetic nerve activity (RSNA), which enhances vascular tone in the kidneys and impairs the physiological regulation of blood pressure. Given the fact that RSNA can increase AngII type 1 (AT1) receptor expression, we speculate that increased baseline RSNA in MS rats results in increased renal AngII system components, predisposing these rats to cardiovascular disease. In an original approach to model the growing epidemic of children with extremely poor dietary lifestyles, we exposed the rats to a high fat diet (HFD) as a secondary stressor. Our data show a fat-induced increase in blood pressure develops in rats exposed to ELS compared to control rats. Furthermore, we observed increased plasma leptin, corticosterone, aldosterone and renin activity in MS rats. These compelling data support the hypothesis that ELS impairs maintenance of blood pressure homeostasis in response to "second hits" in adult life. The mentored phase will focus on the investigation of the RSNA and AT1-dependent mechanisms by which ELS exacerbates AngII-induced hypertension in adult rats, followed by the independent phase focused on the study of mechanisms by which ELS exacerbates blood pressure sensitivity to a HFD in adult rats. This novel proposal will investigate the following four aims: (1) to test the hypothesis that increased RSNA impairs renal capacity to control blood pressure in response to chronic AngII infusion in adult MS rats; (2) to test the hypothesis that exaggerated AT1 receptor activation increases renal vasoconstriction and reduces basal renal filtration capacity, enhancing AngII-induced hypertension in adult MS rats; (3) To test the hypothesis that MS increases sensitivity of blood pressure in response to a HFD through a renal mechanism; and (4) To test the hypothesis that HFD increases AngII in adipose tissue and induces AT1 dependent increase in blood pressure in MS rats.

项目摘要 慢性成人疾病，例如高血压，糖尿病或肥胖症，可能是由于早期而出现的 生命压力（EL）。不良儿童事件与增强的心血管反应高度相关 次要压力源，“第二击”。孕产妇分离是一种已建立的慢性行为应力模型 啮齿动物涉及将幼崽与母亲分开3小时/天的啮齿动物。 在基线条件下，成年母体分离（MS）大鼠显示出较低的肾小球滤过率 与对照组相比，未分离的同窝窝，血压没有差异。有趣的是， 肾素引起的肾脏诱导的血管收缩被减弱，但血压下降。 MS大鼠的神经节封锁更大。这些数据表明MS大鼠的交感神经激活增加。在 对比，MS和对照大鼠之间对血管紧张素II（ANGII）的急性压力反应是可比的 而MS大鼠显示出夸张的慢性血管造成的高血压。因此，我们的数据表明ELS 在“第二次命中”之后，会损害肾脏控制血压的能力。总的来说，我们 假设暴露于MS的大鼠显示出增加的肾交感神经活动（RSNA），这是 增强肾脏的血管张力，并损害血压的生理调节。鉴于 RSNA可以增加Angii 1型（AT1）受体表达的事实，我们推测基线增加 MS大鼠中的RSNA导致肾Angii系统成分增加，使这些大鼠倾向于 心血管疾病。 用原始的方法来模拟饮食生活方式极度差的儿童日益流行的方法， 我们将大鼠暴露于高脂饮食（HFD）作为次应力源。我们的数据显示脂肪引起的增加 与对照大鼠相比，暴露于EL的大鼠的血压会发展。此外，我们观察到增加 MS大鼠的血浆瘦素，皮质酮，醛固酮和肾素活性。这些引人入胜的数据支持 响应成人的“第二次命中”的假设会损害血压稳态的维持 生活。 指导阶段将集中于对RSNA和AT1依赖机制的研究 Els加剧了成年大鼠的Angii诱导的高血压，其次是独立阶段。 研究ELS会加剧对成年大鼠HFD的血压敏感性的机制。这本小说 提案将研究以下四个目标：（1）测试增加RSNA损害肾脏的假设 响应成年MS大鼠慢性血管静脉输注的血压的能力； （2）测试 夸张的AT1受体激活的假设增加了肾血管收缩并减少了基础肾脏 过滤能力，增强成年MS大鼠血管诱导的高血压； （3）测试MS的假设 通过肾脏机制提高血压对HFD的敏感性； （4）测试 假设HFD会增加脂肪组织中的Angii并诱导AT 1依赖性血压升高 在MS大鼠中。