Intrinsic Vascular Smooth Muscle Cell Stiffness

描述(申请人提供)：众所周知，血管硬度随着年龄的增长而增加，而年龄对动脉硬度的影响在老年女性中相对受到保护。尽管之前大多数关于衰老对血管调节和僵硬的影响的机制工作都是在啮齿动物模型中进行的，但这些数据可以外推到人类身上的程度受到血管僵硬变化发生寿命的显著差异的限制。关于性别差异与年龄的研究更多地局限在啮齿动物身上，因为即使是年龄很大的啮齿动物，雌激素水平也从不会下降，而且它们也不会经历更年期。人们普遍认为，非人灵长类动物是研究性别差异随年龄增长的最佳模型，因为老年雌性猴子的激素和月经变化与老年人类雌性猴子的变化相似。我们以前的研究和对老年猴的初步数据表明，随着年龄的增长，主动脉的硬度增加，这种衰老变化在雄性比雌性更大，腹主动脉(AA)和胸主动脉(TA)的这种变化也更大，这只能部分解释细胞外基质(ECM)的变化。在这里，我们将检验这一新的假设，即血管平滑肌细胞(VSMCs)的内在机制以及VSMC-ECM相互作用的改变也有助于老年男性，特别是AA患者主动脉僵硬的增加，反之，有助于保护绝经前女性的主动脉。初步数据表明，老年男性(OM)培养的VSMC硬度增强，与年轻男性(YM)相比，OM衰老的VSMC数量增加，尤其是在AA中，这一假说得到支持。具体地说，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)和人造组织模型来确定年龄和性别对VSMC僵硬和衰老的影响。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之间主动脉僵硬的区域性差异。

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.