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Early Life Stress & Chronic Control of Blood Pressure

早期生活压力

基本信息

批准号：
8469570
负责人：
Analia Loria
金额：
$ 9.07万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-15 至 2013-09-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8469570
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

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：慢性成人疾病，如高血压、糖尿病或肥胖，可能是早期生活压力（ELS）的结果。儿童期不良事件与心血管对次级压力源（“第二次打击”）的反应增强高度相关。母体分离是啮齿类动物慢性行为应激的一种已建立的模型，涉及从出生后第2-14天每天3小时将幼仔与其母亲分离。与对照、未分离的同窝出生大鼠相比，成年母体分离（MS）大鼠在基线条件下显示出较低的肾小球滤过率，血压无差异。有趣的是，苯肾上腺素诱导的肾脏血管收缩减弱，但神经节阻滞引起的血压下降更大的MS大鼠。这些数据表明MS大鼠的交感神经激活增加。相比之下，急性升压反应血管紧张素II（AngII）之间的MS和对照组大鼠，而MS大鼠表现出夸张的慢性血管紧张素II诱导的高血压。因此，我们的数据表明，ELS损害了肾脏在“二次打击”后控制血压的能力。综上所述，我们假设暴露于MS的大鼠显示肾交感神经活动（RSNA）增加，这增强了肾脏中的血管张力并损害了血压的生理调节。鉴于RSNA可以增加血管紧张素Ⅱ 1型（AT 1）受体表达的事实，我们推测，增加基线RSNA MS大鼠的结果增加肾脏血管紧张素Ⅱ系统的组成部分，易患心血管疾病。在一个原始的方法来模拟日益流行的儿童与极端贫困的饮食生活方式，我们暴露了大鼠高脂肪饮食（HFD）作为次要的压力。我们的数据显示，与对照组大鼠相比，暴露于ELS的大鼠中出现脂肪诱导的血压升高。此外，我们观察到MS大鼠血浆瘦素，皮质酮，醛固酮和肾素活性增加。这些令人信服的数据支持ELS损害维持血压稳态的假设，以应对成年生活中的“二次打击”。指导阶段将重点研究RSNA和AT 1依赖性机制，ELS通过该机制加重成年大鼠AngII诱导的高血压，随后是独立阶段，重点研究ELS通过该机制加重成年大鼠对HFD的血压敏感性。这个新的建议将调查以下四个目标：（1）测试的假设，增加 RSNA损害成年MS大鼠对慢性AngII输注的肾控制血压的能力;（2）检验过度的AT 1受体活化增加肾血管收缩并降低基础肾滤过能力，增强成年MS大鼠AngII诱导的高血压的假设;（3）验证MS通过肾脏机制增加血压对HFD的敏感性的假设;（4）验证HFD增加MS大鼠脂肪组织AngII并诱导AT 1依赖性血压升高的假设。