Aging, the Baroreflex and Ang-(1-7) Receptors

衰老的典型特征是心血管调节的进行性损害，其可包括交感神经流出增加、迷走神经活动减少和血管扩张性降低。这些心血管变化还与肾素-血管紧张素（Ang）系统（RAS）活性降低和胰岛素抵抗相关。项目4的总体目标是确定胰岛素和RAS的特定组分如何共同作用，作为改变心血管调节的主要贡献者，最终导致收缩压升高以及衰老过程中高胰岛素血症和高血糖症的恶化。我们专注于对方 孤束核（nTS）中的Ang II和Ang-（1-7）调节交感神经和副交感神经流出的压力感受器反射控制的作用。这些研究将确定胰岛素如何与这两种肽协同作用或相反，通过延髓和下丘脑的心血管相关区域的作用，在自主神经流出的神经调节中起作用。我们的实验策略将利用该项目成员的综合专业知识来定义神经系统、肽受体途径和代谢组分，这些组分相互作用以解释心血管调节的改变 在老化过程中。具体目的1研究了内源性Ang-（1-7）促进压力感受器反射功能的作用随着年龄的增长而减弱的假设，使得Ang II和胰岛素的作用不受对抗，从而有助于减少心脏迷走神经流出，增强交感神经流出和高血压。实验将集中在nTS，下丘脑室旁核，和延髓头端腹外侧作为关键网站在大脑中的血管紧张素肽和胰岛素的行动在衰老过程中的变化。作为一种机制，有助于改变作用的血管紧张素肽和胰岛素在老化的具体目标2将测试的假设，血管紧张素-（1-7）在脑组织中随着年龄的减少，导致一个转变的功能或表达的血管紧张素II和胰岛素。由于受体构成了细胞内的关键功能成分， 具体目标3将评估Ang II和Ang-（1-7）受体经历动态调节的假设，所述动态调节部分地由这两种肽的组织水平的改变确定。特别是，所提出的实验将建立AT 1b受体和mas孤儿受体之间的功能相互作用，作为响应Ang-（1-7）的关键元件。拟议的实验利用了一种缺乏脑血管紧张素原（ASrAogen）生产的转基因大鼠模型，我们表明，在相同的时间范围内，该模型不会表现出与Sprague-Dawley大鼠衰老相关的心血管损伤。

Aging is typified by progressive impairments in cardiovascular regulation that may include increased sympathetic outflow, reduced vagal activity and reduced vascular distensibility. These cardiovascular changes are also associated with decreased activity of the renin-angiotensin (Ang) system (RAS) and insulin resistance. The over-arching goal of Project 4 is to define how insulin and specific components of the RAS act together as major contributors to altered cardiovascular regulation that ultimately lead to elevated systolic pressure and exacerbation of hyperinsulinemia and hyperglycemia during the course of aging. We focus on the opposing actions of Ang II and Ang-(1-7) in the nucleus of the solitary tract (nTS) to modulate the baroreceptor reflex control of sympathetic and parasympathetic outflow. The investigations will define how insulin may act in concert with or opposition to these two peptides in neural regulation of autonomic outflow via actions at cardiovascular relevant regions of the medulla oblongata and hypothalamus. Our experimental strategy will draw upon the combined expertise of members of the Project to define the neural systems, peptide receptor pathways, and metabolic components that interact to account for modification of cardiovascular regulation during aging. Specific Aim 1 investigates the hypothesis that the role of endogenous Ang-(1-7) to facilitate baroreceptor reflex function diminishes with aging, such that the effects of Ang II and insulin are unopposed, thereby contributing to reduced cardiac vagal outflow, enhanced sympathetic outflow, and hypertension. Experiments will focus on the nTS, paraventricular nucleus of the hypothalamus, and rostral ventrolateral medulla as key sites in the brain where actions of Ang peptides and insulin change during the aging process. As one mechanism contributing to the altered roles of Ang peptides and insulin during aging Specific Aim 2 will test the hypothesis that Ang-(1-7) in brain tissue diminishes with age, leading to a shift in the function or expression of Ang II and insulin. Since receptors constitute a key functional component in the aforementioned central regulation of cardiovascular function during aging, Specific Aim 3 will assess the hypothesis that Ang II and Ang-(1-7) receptors undergo a dynamic regulation, in part, determined by alterations in the tissue levels of these two peptides. In particular, the proposed experiments will establish the functional interactions that develop between the AT1b receptor and the mas orphan receptor as key elements responsive to Ang-(1-7). The proposed experiments utilize a transgenic rat model deficient in the production of brain angiotensinogen (ASrAogen), which we show does NOT exhibit cardiovascular impairments over the same time frame typically associated with aging in Sprague-Dawley rats.