Heart and vascular responses across the lifespan in Ts65Dn mice, a model of Down syndrome

摘要 唐氏综合症(DS)是导致智力残疾的最常见的染色体原因，原因是 21号染色体基因的三倍体。患有精神障碍的人不仅表现出认知缺陷，还表现出 包括心血管改变和肺动脉高压在内的病症。降低休息时的血压和 对运动和其他应激源的反应在DS中很普遍。减弱的心血管反应 DS患者的日常生活活动是自主调节的，但可能包括其他因素，如内皮 功能障碍。这些心血管发现因以下事实而变得复杂：DS受到保护，不受 动脉硬化。因此，引起DS心血管改变的机制是多方面的。 这群人。目前还没有一个适当发展的心血管模型来研究这些 重要的临床问题，尽管三体动物模型确实存在。我们强劲的初步数据显示 受限患者平均动脉压、舒张压和收缩压降低 Ts65Dn小鼠，DS模型。自由活动的Ts65Dn小鼠的心率低于野生型(WT)。已被占用 总之，这些数据表明，在Ts65Dn小鼠身上观察到的心血管模式的改变可能是 代表患有牙周炎的人。这项探索性拨款申请旨在通过一系列生理上的 实验表明，Ts65Dn小鼠是研究心脏和血压差异的合适模型。 DS.这项建议中描述的实验将进一步检查Ts65Dn小鼠的心血管变化 通过有意识和减少准备，包括自主神经系统的贡献和 内皮功能失调是血管张力和心输出量减弱的潜在机制。特定的 目的1比较WT和Ts65Dn小鼠在3、6和12岁时的心血管状况和血管生理学 几个月大的孩子。血压和心率将通过无线电遥测在整个昼夜周期中进行量化， 我们将进一步区分自主血压控制中可能存在的机制差异 对清醒小鼠交感和副交感神经系统的药理阻断。动脉 麻醉小鼠的僵硬程度将使用脉搏波速度和心率变异性进行量化。 监测清醒和麻醉实验中的自主神经音调。动脉等长张力的应用 体外实验将比较主动脉和肠系膜动脉的内皮依赖性和非依赖性血管扩张。 具体目标2将用WT的活体压力-容量环来量化压力反射敏感性和心功能 和Ts65Dn小鼠。所有AIMS将研究3个月、6个月和12个月大的雄性和雌性小鼠 在该模型中，进一步将年龄和性别描述为生物变量。因为患有DS的人表现出 加速衰老的特点了解心脏功能和血压的变化 WT与Ts65Dn的反应随年龄增长而变化。总体而言，该项目将提供对 DS的心血管调节，目的是改善患有这种疾病的人的生活质量。 好了！

ABSTRACT Down Syndrome (Ds) is the most common chromosomal cause of intellectual disability that results from triplication of chromosome 21 genes. Persons with Ds demonstrate cognitive deficits in addition to co- morbidities including cardiovascular alterations and pulmonary hypertension. Lower blood pressure at rest and in response to exercise and other stressors are prevalent in Ds. The attenuated cardiovascular reactions to activities of daily living in Ds are autonomically mediated, but likely include other factors such as endothelial dysfunction. These cardiovascular findings are complicated by the fact that Ds is protected from atherosclerosis. Therefore, the mechanisms responsible for cardiovascular alterations in Ds are multifaceted in this population. At this time there is not an appropriately developed cardiovascular model to investigate these important clinical concerns, although a trisomic animal model does exist. Our robust preliminary data reveal attenuated mean arterial blood pressure, diastolic blood pressure and systolic blood pressure in restrained Ts65Dn mice, a model of Ds. Freely moving Ts65Dn mice have lower heart rate than wild-type (WT). Taken together, these data suggest the altered cardiovascular patterns observed in Ts65Dn mice may be representative of people with Ds. This exploratory grant application aims to verify, via a series of physiological experiments, that the Ts65Dn mouse is an appropriate model to study heart and blood pressure differences in Ds. The experiments described in this proposal will further examine cardiovascular alterations in Ts65Dn mice through conscious and reduced preparations, including autonomic nervous system contributions and endothelial dysregulation as a potential mechanism of attenuated vascular tone and cardiac output. Specific Aim 1 will compare the cardiovascular profile and vascular physiology of WT and Ts65Dn mice at 3, 6 and 12 months of age. Blood pressure and heart rate will be quantified across the circadian cycle via radiotelemetry, and we will further distinguish possible mechanistic differences in autonomic control of blood pressure with pharmacological blockade of the sympathetic and parasympathetic nervous system in conscious mice. Arterial stiffness will be quantified in anesthetized mice using pulse wave velocity, and heart rate variability will be used to monitor autonomic tone in both conscious and anesthetized experiments. Arterial isometric tension using an in vitro setup will compare endothelial dependent and independent vasodilation of aorta and mesenteric artery. Specific Aim 2 will quantify baroreflex sensitivity and cardiac function with in vivo pressure-volume loops in WT and Ts65Dn mice. All aims will study male and female mice at 3 months, 6 months and 12 months of age to further describe aging and sex as biological variables in this model. Since individuals with Ds demonstrate characteristics of accelerated aging it will be important to know how heart function and blood pressure responses change with advancing age in WT vs. Ts65Dn. Overall, this project will provide insight into cardiovascular regulation in Ds with the objective of improving the quality of life of persons with this condition. !