Early Life Stress & Chronic Control of Blood Pressure

描述(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。儿童时期的不良事件与心血管对次要应激源的增强反应高度相关，次要应激源是“二次打击”。母体分离是啮齿类动物慢性行为压力的一个既定模型，包括在生命的第2-14天每天3小时将幼崽与它们的母亲分开。在基线条件下，成年母体分离(MS)大鼠的肾小球滤过率低于未分离的对照仔鼠，但血压没有差异。有趣的是，在MS大鼠中，苯肾上腺素引起的肾脏血管收缩作用减弱，但神经节阻断引起的血压下降更大。这些数据表明MS大鼠的交感神经活动增加。相反，血管紧张素II(AngII)的急性升压反应在MS大鼠和对照组之间是相似的，而MS大鼠表现出夸大的慢性Angii诱导的高血压。因此，我们的数据表明ELS在“二次打击”后损害了肾脏控制血压的能力。综上所述，我们假设暴露于MS的大鼠表现出肾脏交感神经活动(RSNA)增加，这增强了肾脏的血管张力，损害了血压的生理调节。鉴于RSNA可以增加血管紧张素转换酶1型(AT1)受体的表达，我们推测MS大鼠基线RSNA增加会导致肾脏血管紧张素系统成分增加，从而使这些大鼠易患心血管疾病。在对饮食生活方式极差的儿童日益流行的模型进行建模的原始方法中，我们将大鼠暴露在高脂肪饮食(HFD)中作为次要应激源。我们的数据显示，与对照组相比，暴露于ELS的大鼠出现了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、醛固酮和肾素活性升高。这些令人信服的数据支持这一假设，即ELS损害了血压稳态的维持，以回应成年生活中的“二次打击”。指导阶段将重点研究ELS加剧成年大鼠血管紧张素Ⅱ诱导的高血压的RSNA和AT1依赖的机制，随后的独立阶段重点研究ELS加剧成年大鼠对HFD的血压敏感性的机制。这一新的提议将调查以下四个目的：(1)检验增加的假设 目的：(1)验证血管紧张素转换酶激活抑制血管紧张素转换酶AT1受体激活增加肾脏血管收缩并降低基础肾滤过能力，从而加强血管紧张素转换酶诱导的成年MS大鼠高血压的假说；(3)验证MS通过肾脏机制增加对HFD反应的血压敏感性的假说；以及(4)检验HFD增加脂肪组织AngiI并诱导AT1依赖的MS大鼠血压升高的假说。

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.