Intrinsic Vascular Smooth Muscle Cell Stiffness

项目总结： 众所周知，血管硬度随着年龄的增长而增加，而衰老对动脉硬度的影响 在老年女性中相对受到保护。尽管大多数先前关于衰老影响的机械性工作 血管调节和僵硬已经在啮齿动物模型中进行了，这些数据可以在多大程度上 对人类的推断受到寿命的显著差异的限制，血管的变化 僵硬发展。关于性别差异与年龄的关系的研究更多地局限于啮齿动物，因为 即使是年龄很大的啮齿动物，雌激素水平也不会下降，而且它们不会经历更年期。它是 普遍认为非人类灵长类动物是研究性别随年龄增长差异的最佳模型，因为 老年雌性猴子的荷尔蒙和月经的变化与老年人类雌性猴子相似。 我们之前的研究和对老年猴子的初步数据已经证明，主动脉的僵硬 随着年龄的增长，这种衰老变化在男性比女性更大，在老年人中也更大 腹主动脉(AA)和胸主动脉(TA)，这只能部分解释细胞外的差异 矩阵(ECM)。在这里，我们将检验一种新的假说，即血管平滑肌的内在机制 细胞(VSMC)以及VSMC-ECM相互作用的改变也有助于增加血管内皮细胞的刚性。 老年男性的主动脉，尤其是AA，反过来有助于绝经前的保护 女性。这一假说得到了初步数据的支持，这些数据表明VSMC在 培养的老年男性(OM)主动脉显示衰老的VSMC的数量在OM中增加 与年轻男性(Ym)相比，尤其是在AA中。具体地说，我们将通过两个例子来检验我们的假设 接近了。在第一种方法中，我们将确定VSMC僵硬和衰老是如何受到年龄的影响的 和性别使用原子力显微镜(AFM)和人造组织模型。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的区域差异。 硬度介于TA和AA之间。

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.