Intrinsic Vascular Smooth Muscle Cell Stiffness

描述（由申请人提供）：众所周知，血管硬度随着年龄的增长而增加，并且老年女性中年龄对动脉硬度的影响相对受到保护。尽管大多数关于衰老对血管调节和硬度的影响的先前机制性工作已经在啮齿动物模型中进行，但是这些数据可以外推到人类的程度受到血管硬度变化发展的寿命的显著差异的限制。在啮齿类动物中，关于衰老的性别差异的研究更加有限，因为即使在非常老的啮齿类动物中，雌激素水平也不会下降，而且它们不会经历更年期。人们普遍认为，非人类灵长类动物是研究衰老性别差异的最佳模型，因为老年雌性（OF）猴子的激素和月经变化与老年人类女性相似。我们以前的研究和初步数据显示，主动脉的硬度随着年龄的增长而增加，这种老化变化在雄性中比雌性大，在腹主动脉（AA）中也比胸主动脉（TA）大得多，这只能部分解释为细胞外基质（ECM）的变化。在这里，我们将测试新的假设，在血管平滑肌细胞（VSMCs）的内在机制以及VSMC-ECM相互作用的改变也有助于增加刚度的主动脉在老年男性，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，老年男性（OM）睾丸培养物中VSMC的硬度增强，并显示OM中衰老VSMC的数量比年轻男性（YM）增加，特别是在AA中。具体来说，我们将通过两种方法来检验我们的假设。在第一种方法中，我们将使用原子力显微镜（AFM）和人工组织模型来确定年龄和性别如何影响VSMC的刚度和衰老。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TA和AA之间主动脉僵硬度的区域差异。

DESCRIPTION (provided by applicant): 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.