Intrinsic Vascular Smooth Muscle Cell Stiffness

项目概要： 众所周知，血管硬度随着年龄的增长而增加，并且年龄对动脉硬度的影响 在老年女性中相对受到保护。虽然大多数先前的关于衰老影响的机械工作， 在啮齿动物模型中进行了血管调节和僵硬的研究，这些数据可以在多大程度上被 外推到人类是有限的，在寿命的显着差异，其中血管的变化， 刚度发展。在啮齿类动物中，关于衰老的性别差异的研究更为有限，这是因为 雌激素水平从来没有下降，即使在非常老的啮齿动物，他们没有经历更年期。是 普遍认为，非人类灵长类动物是研究性别差异与衰老的最佳模型，因为 老年雌性（OF）猴子的激素和月经的变化与老年人类女性的变化相似。 我们以前的研究和对老龄猴子的初步数据表明， 随着年龄的增长而增加，这种年龄变化在男性中比女性更大，在女性中也更大。 腹主动脉（AA）与胸主动脉（TA），这只能部分由细胞外基质的差异来解释 矩阵（ECM）。在这里，我们将测试新的假设，在血管平滑肌的内在机制， 细胞（VSMCs）以及VSMC-ECM相互作用的改变也有助于增加的刚度。 主动脉在老年男性，特别是AA，相反，有助于保护绝经前 女性这一假设得到了初步数据的支持，初步数据表明， 从老年男性（OM）睾丸培养，显示衰老的VSMC数量增加， 与年轻男性（YM）相比，尤其是AA。具体来说，我们将通过两个方面来检验我们的假设。 接近。在第一种方法中，我们将确定VSMC的刚度和衰老是如何受到年龄的影响 和性别使用原子力显微镜（AFM）和人工组织模型。在第二种方法中， 我们将在体内和体外确定这些因素如何解释主动脉瓣狭窄的区域差异。 TA和AA之间的刚度。

PROJECT SUMMARY: It is well known that vascular stiffness increases with aging, and that the effects of aging on arterial stiffness are relatively protected in older women. Although most prior mechanistic work on the effects of aging on vascular regulation and stiffness has been conducted in rodent models, the extent to which these data can be extrapolated to humans is limited by the marked differences in lifespan over which changes in vascular stiffness develop. Studies of gender differences with aging are even more limited in rodents, due to the fact that the estrogen levels never decline even in very old rodents, and they do not go through menopause. It is generally agreed that non-humans primates are the best models to study gender differences with aging, since the changes in hormones and menstruation in old female (OF) monkeys parallel those in older human females. Our previous studies and preliminary data in aging monkeys have demonstrated that the stiffness of the aorta increases with aging and this aging alteration is greater in males than females, and also much greater in the abdominal aorta (AA) vs. the thoracic aorta (TA), which is only partially explained by variance in extracellular matrix (ECM). Here, we will test the novel Hypothesis that intrinsic mechanisms in the vascular smooth muscle cells (VSMCs) as well as alterations in VSMC-ECM interaction also contribute to the increased stiffness of the aorta in older males, particularly the AA, and conversely, contribute to the protection in pre-menopausal females. This Hypothesis is supported by Preliminary Data demonstrating enhanced stiffness of VSMC in culture from old male (OM) aortas and showing that the number of senescent VSMC increases in OM compared to young males (YM), particularly in AA. Specifically, we will test our Hypothesis through two approaches. In the first approach, we will determine how VSMC stiffness and senescence are affected by age and gender using atomic force microscopy (AFM) and also an artificial tissue model. In the second approach, we will determine both in vivo and in vitro how these factors may explain the regional differences in aortic stiffness between TA and AA.