Early Life Stress & Chronic Control of Blood Pressure

项目总结 慢性成人疾病，如高血压、糖尿病或肥胖症，可能是由于过早的 生活压力(ELS)。儿童时期的不良事件与心血管反应增强高度相关 二次应激源，“二次打击”。母体分离是慢性行为应激的一个既定模型 啮齿动物，在生命的第2-14天，每天3小时将幼崽与它们的母亲分开。 成年母体分离(MS)大鼠在基线条件下肾小球滤过率较低 与对照组相比，未分离的窝产仔，血压没有差异。有趣的是， 苯肾上腺素引起的肾脏血管收缩作用减弱，但其引起的血压下降 MS大鼠的神经节阻滞作用更强。这些数据表明MS大鼠的交感神经活动增加。在……里面 相比之下，MS大鼠和对照组大鼠对血管紧张素II(AngII)的急性升压反应是相似的 而MS大鼠则表现出夸大的慢性血管紧张性高血压。因此，我们的数据表明ELS 在“二次打击”后，损害肾脏控制血压的能力。总而言之，我们 假设暴露于MS的大鼠表现出肾脏交感神经活动(RSNA)增加，这 增强肾脏的血管张力，损害血压的生理调节。给定 事实上，RSNA可以增加血管紧张素Ⅱ1型(AT1)受体的表达，我们推测增加的基线 多发性硬化大鼠的RSNA导致肾脏血管系统成分增加，使这些大鼠易患 心血管疾病。 在对饮食生活方式极其糟糕的儿童日益流行的模型进行建模的独创方法中， 我们将大鼠暴露在高脂饮食(HFD)中作为次要应激源。我们的数据显示，脂肪诱导的 与对照组相比，暴露于ELS的大鼠血压升高。此外，我们观察到增加了 多发性硬化大鼠血浆瘦素、皮质酮、醛固酮及肾素活性。这些令人信服的数据支持 ELS损害成人血压内稳态维持对“二次打击”反应的假设 生活。 指导阶段将集中研究RSNA和AT1依赖的机制，通过这些机制 ELS加重成年大鼠血管紧张素Ⅱ诱导的高血压，随后的独立阶段集中在 ELS加重成年大鼠对HFD的血压敏感性的机制研究。这部小说 提案将调查以下四个目标：(1)检验RSNA增加损害肾脏的假设 成年MS大鼠对慢性血管紧张素Ⅱ输注反应的血压控制能力；(2)测试 夸大AT1受体激活增加肾血管收缩和减少基础肾的假说 过滤能力，增强血管紧张素Ⅱ诱导的成年MS大鼠的高血压；(3)验证MS的假说。 通过肾脏机制增加对HFD反应的血压敏感性；以及(4)测试 假设HFD增加脂肪组织中的Angii并导致AT1依赖性血压升高 多发性硬化症大鼠。

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.