Early life stress and chronic control of blood pressure

早期生活压力和血压的长期控制

基本信息

批准号：
8226337
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 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8226337
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，例如高血压、糖尿病或肥胖症，可能是由于早期生活压力（ELS）而产生的。童年不良事件与心血管对次要压力源（“第二次打击”）的反应增强高度相关。母亲分离是啮齿类动物慢性行为压力的一种既定模型，其中包括从出生后第 2-14 天将幼崽与母亲分开 3 小时/天。与未分离的对照同窝大鼠相比，成年母体分离（MS）大鼠在基线条件下表现出较低的肾小球滤过率，但血压没有差异。有趣的是，多发性硬化症大鼠中去氧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幅度更大。这些数据表明多发性硬化症大鼠的交感神经激活增加。相比之下，MS 大鼠和对照大鼠对血管紧张素 II (AngII) 的急性升压反应相当，而 MS 大鼠表现出过度的慢性 AngII 诱导的高血压。因此，我们的数据表明，ELS 会损害肾脏在“第二次打击”后控制血压的能力。综上所述，我们假设暴露于 MS 的大鼠表现出肾交感神经活动 (RSNA) 增加，从而增强肾脏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，我们推测 MS 大鼠基线 RSNA 增加会导致肾脏 AngII 系统成分增加，从而使这些大鼠易患心血管疾病。在模拟饮食生活方式极其不良的儿童日益流行的原始方法中，我们让老鼠接受高脂肪饮食（HFD）作为次要压力源。我们的数据显示，与对照大鼠相比，暴露于 ELS 的大鼠会出现由脂肪引起的血压升高。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这样的假设：ELS 会损害血压稳态的维持，以应对成人生活中的“第二次打击”。指导阶段将重点研究 ELS 加剧成年大鼠 AngII 诱导的高血压的 RSNA 和 AT1 依赖性机制，随后的独立阶段重点研究 ELS 加剧大鼠对 HFD 的血压敏感性的机制。成年大鼠。这项新颖的提案将研究以下四个目标：（1）检验增加的假设 RSNA 会损害成年 MS 大鼠慢性 AngII 输注时肾脏控制血压的能力； (2) 验证 AT1 受体过度激活会增加肾血管收缩并降低基础肾滤过能力，从而增强成年 MS 大鼠中 AngII 诱导的高血压的假设； (3) 检验 MS 通过肾脏机制增加对 HFD 的血压敏感性的假设； (4) 检验 HFD 增加 MS 大鼠脂肪组织中的 AngII 并诱导 AT1 依赖性血压升高的假设。