Aging Effects on Cardiovascular Function

众所周知，血管硬度随着年龄的增长而增加，但其中涉及的机制尚不清楚，部分原因可能是缺乏适当的模型。事实上，大多数关于衰老的研究都是在啮齿动物模型上进行的，或者是在患有与衰老相关的疾病的人类身上进行的，例如糖尿病或动脉粥样硬化。灵长类动物模型是独一无二的，因为它在系统发育上更接近人类，但没有相关的衰老疾病。在过去的资助期间，我们开发了这个灵长类模型，并发现了支持续签申请的新的初步数据。我们的初步数据表明，与雄性猴子相比，雌性猴子似乎相对免受与衰老相关的血管变化的影响。随着年龄的增长，血管壁的组成以及对拟交感神经胺的反应也有很大的性别差异。因此，该提案中的一个重要主题包括审查老龄化过程中的性别差异。我们将检验三个假说：1)老年雄性猴子的血管硬度增加，但老年雌性猴子的血管僵硬相对受到保护。然而，重要的是，我们的假设是 血管僵硬不能完全归因于胶原和弹性蛋白的变化。因此，我们提出了两个新的假设：a)血管硬度随年龄增加的一种机制与小窝蛋白和微管聚合有关；随着年龄的增长，血管硬度增加的部分原因在于平滑肌细胞的水平。在这些研究中，将使用原子力显微镜评估血管平滑肌的硬度；2)基因表达模式的差异可以解释性别差异 3)蛋白质的表达模式必须存在性别差异，这可以解释参与血管僵硬发展的不同。这些假设和目标将使用多学科方法进行研究，以最大限度地利用这一新的灵长类模型。

It is well known that vascular stiffness increases with aging, yet the mechanisms involved are poorly understood, potentially due, in part, to lack of appropriate models. Indeed, the majority of research in aging has been conducted in rodent models or in humans with associated diseases of aging, e.g., diabetes or atherosclerosis. The primate model is unique because it is phylogenetically closer to humans, yet does not have associated diseases of aging. Over the past funding period, we have developed this primate model and have uncovered novel preliminary data supporting the renewal application. Our preliminary data indicate that female monkeys appear relatively protected from the vascular changes associated with aging compared with males. There are major gender differences observed in the composition of the vascular wall with aging and also in response to sympathomimetic amines. Accordingly, one important theme in this proposal includes examination of gender differences during aging. We will examine three hypotheses 1) Vascular stiffness increases in old male monkeys, but is relatively protected in old female monkeys. However, importantly, our hypothesis is that increases in vascular stiffness cannot be ascribed entirely to changes in collagen and elastin. Therefore, we propose two novel hypotheses: a.) that one mechanism of increased vascular stiffness with age involves caveolin and microtubules polymerization; and B.) that in part the increase in vascular stiffness with age resides at the level of the smooth muscle cell. For these studies, vascular smooth muscle stiffness will be assessed using an atomic force microscope; 2) Differences in the pattern of the expression of genes could explain the gender differences involved in the development of vascular stiffness; and 3) Gender differences must exist in the pattern of expression of proteins that could explain the differences involved in the development of vascular stiffness. These hypotheses and aims will be investigated using a multidisciplinary approach to maximally utilize this novel primate model.