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

摘要 唐氏综合症（Ds）是最常见的染色体原因的智力残疾，结果是 21号染色体基因的三倍。患有Ds的人除了表现出共同的认知缺陷外， 包括心血管改变和肺动脉高压的发病率。降低休息时的血压， 在运动和其他压力源的反应中，D.减弱的心血管反应， Ds患者的日常生活活动是由血管介导的，但可能包括其他因素，如内皮细胞 功能障碍这些心血管的发现是复杂的事实，即Ds是保护， 动脉粥样硬化因此，导致Ds心血管改变的机制是多方面的， 这个人口。目前还没有适当开发的心血管模型来研究这些 重要的临床问题，尽管确实存在三体动物模型。我们可靠的初步数据显示 抑制性舒张压和收缩压降低 Ts 65 Dn小鼠，建立Ds.自由移动的Ts 65 Dn小鼠的心率低于野生型（WT）。采取 总之，这些数据表明，在Ts 65 Dn小鼠中观察到的心血管模式的改变可能是 D的代表人物。这项探索性的拨款申请旨在通过一系列的生理学研究， Ts 65 Dn小鼠是研究心脏和血压差异的合适模型， DS.本提案中描述的实验将进一步检查Ts 65 Dn小鼠的心血管改变 通过有意识和减少准备，包括自主神经系统的贡献， 内皮失调是血管张力和心输出量减弱的潜在机制。具体 目的1将比较WT和Ts 65 Dn小鼠在3、6和12小时的心血管特征和血管生理学 月龄。血压和心率将通过无线电遥测在昼夜节律周期中进行量化， 我们将进一步区分自主控制血压的可能机制差异， 在清醒小鼠中交感神经和副交感神经系统的药理学阻断。动脉 将使用脉搏波速度和心率变异性在麻醉小鼠中定量硬度 在清醒和麻醉的实验中监测自主神经张力。动脉等长张力测定 体外设置将比较主动脉和肠系膜动脉内皮依赖性和非依赖性血管舒张。 Specific Aim 2将在WT中使用体内压力-容积环量化压力反射敏感性和心脏功能 和Ts 65 Dn小鼠。所有目标将研究3个月、6个月和12个月大的雄性和雌性小鼠， 进一步将年龄和性别描述为该模型中的生物变量。由于患有D的人表现出 加速老化的特点，重要的是要知道如何心脏功能和血压 WT与Ts 65 Dn的反应随年龄增长而变化。总的来说，该项目将提供深入了解 心血管调节的目的是提高生活质量的人与这种条件。 !

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. !