Intrinsic Stiffness of Aortic Vascular Smooth Muscle Cell in the Development of Hypertension

 描述(申请人提供)：高血压是人类最常见的年龄相关性慢性疾病之一，影响全球超过10亿人。尽管几十年来进行了大量的研究工作，但对于这种疾病的主要原因仍然没有达成共识，其治疗被认为是强制性的。随着年龄的增长，血压的升高与主动脉僵硬基本一致，这一点已被广泛接受，然而，其机制却知之甚少。以往的研究大多集中在细胞外基质(ECM)或内皮调控方面，我们先前的研究和初步数据显示，在衰老和高血压时，主动脉血管平滑肌细胞(VSMCs)的僵硬也是导致主动脉僵硬的原因之一。家长基金的重点是年轻的高血压成年人，提出了一个新的概念，即高血压的一个关键机制可能存在于VSMC。在本次修订应用中，我们将这一新概念扩展到老年动物模型，以研究年龄对血管变化和高血压发展的影响，特别是区分年龄相关性变化和高血压相关性主动脉VSMC力学特性的变化。我们对这一修订建议的假设是，年龄引起的主动脉VSMCs固有僵硬的改变和VSMC-ECM相互作用不同于年轻人的高血压，并且是主动脉僵硬增加的独立贡献者，从而加速了老年人高血压的发展。本研究的目的是明确AGE诱导的VSMC改变在老年高血压发生发展中的意义，并确定介导这些改变的潜在细胞/分子机制，从而为寻找新的老年高血压的预防和治疗方法提供依据。通过使用与母公司拨款相同的复杂实验系统，包括整个动物、分离的血管、重组组织和单细胞观察，我们将通过两个老年高血压大鼠模型，自发性高血压大鼠和血管紧张素性高血压大鼠，验证我们的假设，具体目的如下：在特定目标A，我们将纳入一个策略，以确定主动脉VSMC硬度和VSM-ECM相互作用的年龄相关性变化，以及这些年龄诱导的变化是否独立于血压升高。在特定的目标B中，我们将确定这些变化对老年动物高血压发展的影响及其机制。如果这一假设是正确的，本研究将导致进一步研究治疗老年高血压的新策略，例如，使用针对VSMC自身水平的药物靶向药物，以降低老年引起的主动脉僵硬，从而防止老年人收缩压和脉压的升高。

 DESCRIPTION (provided by applicant): PROJECT SUMMARY Hypertension is one of the most common age associated chronic disorders in human and affects more than 1 billion people worldwide. Despite intense research efforts over several decades, there is still no consensus on what are the primary causes of this disorder and its treatment is considered mandatory. It has been widely accepted that the increase in blood pressure with advancing age is mostly consistent with aortic stiffness, however, little is known about mechanisms. Most prior work has focused on the extracellular matrix (ECM) or endothelial control, our previous study and Preliminary Data revealed that aortic vascular smooth muscle cells (VSMCs) stiffness also contributes to the increase aortic stiffness in both aging and hypertension. The parent grant, which focuses on young hypertensive adults, presents a novel concept that a key mechanism for hypertension may reside in VSMC. In this revision application, we will extend this new concept to aged animal models to study the influence of age on vascular changes and the development of hypertension, specifically to differentiate the age dependent changes and hypertension dependent changes in aortic VSMC mechanical properties. Our hypothesis of this revision proposal is that age induced alterations of the intrinsic stiffness of VSMCs and VSMC-ECM interaction in the aorta differs from those with HT in young adults and acts as an independent attributor to increased aortic stiffness and subsequently accelerates the development of hypertension in older individuals. The goal of this proposal is to identify the significance of age induced alterations of VSMC in the development of HT in elderly, and to determine potential cellular/molecular mechanisms mediating these changes, which could then be investigated to uncover novel preventive and therapeutic approaches for age related hypertension. By using the same complex experimental systems as proposed in the parent grant that includes whole animal, isolated vessel, reconstituted tissue and the single cell observations, we will test our Hypothesis through two aged hypertensive rat models, spontaneously hypertensive rats and angiotensin induced hypertensive rats, by the following Specific Aims: In Specific Aim A, we will incorporate a strategy to identify the age dependent changes of aortic VSMC stiffness and VSM- ECM interaction and whether these age induced alterations are independent of the elevated blood pressure. In Specific Aim B, we will determine the influence of these changes on the development of hypertension in aged animals and the mechanisms involved. If this hypothesis is correct, this study will lead to further investigation o novel therapeutic strategy for age related hypertension, e.g. with pharmaceutical targets agents directed at the level of the VSMC itself, to reduce age induced aortic stiffness and thus prevent the increase of systolic blood pressure and pulse pressure in elderly.