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

高血压发展过程中主动脉血管平滑肌细胞的固有硬度

• 批准号: 8959886
• 负责人: Hongyu Qiu
• 金额: $ 12.95万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8959886
• 关键词: Adult; Affect; Age; Aging; Angiotensins; Animal Model; Animals; Aorta; Aortic Aneurysm; Arteries; Atomic Force Microscopy; Automobile Driving; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cell Adhesion Molecules; Cells; Chronic Disease; Complex; Consensus; Cytoskeleton; Data; Dependence; Development; Diastolic blood pressure; Disease; Elderly; Extracellular Matrix; Future; Goals; Human; Hypertension; Inbred SHR Rats; Individual; Investigation; Isolated systolic hypertension; Lead; Mechanics; Mediating; Methodology; Microfilaments; Modeling; Molecular; Pharmacologic Substance; Preventive; Property; Pulse Pressure; Rattus; Research; Rho-associated kinase; Risk Factors; Sex Characteristics; Smooth Muscle Myocytes; Stroke; System; Techniques; Testing; Therapeutic; Tissue Model; Tissues; Vascular Diseases; Work; abstracting; age effect; age related; aged; base; insight; normotensive; novel; novel therapeutics; parent grant; prevent; reconstitution; regional difference; research study; young adult

 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.

 描述（由申请人提供）：项目总结高血压是人类最常见的年龄相关慢性疾病之一，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。人们普遍认为，随着年龄的增长，血压升高与主动脉僵硬度基本一致，但对其机制知之甚少。大多数先前的工作都集中在细胞外基质（ECM）或内皮控制，我们以前的研究和初步数据显示，主动脉血管平滑肌细胞（VSMCs）刚度也有助于增加主动脉僵硬在衰老和高血压。家长资助主要针对年轻高血压成年人，提出了一个新概念，即高血压的关键机制可能存在于VSMC中。在本修订申请中，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，特别是区分主动脉VSMC力学特性的年龄依赖性变化和高血压依赖性变化。我们的假设是，年龄引起的VSMCs和VSMC-ECM相互作用的固有刚度在主动脉中的变化不同于那些与HT在年轻的成年人，并作为一个独立的归因于主动脉僵硬度增加，随后加速老年人高血压的发展。本研究的目的是明确年龄诱导的VSMC改变在老年人HT发生中的意义，并确定介导这些变化的潜在细胞/分子机制，然后研究这些机制以发现新的预防和治疗方法。通过使用与母基金中提出的相同的复杂实验系统，包括整个动物、离体血管、重建组织和单细胞观察，我们将通过两种老年高血压大鼠模型（自发性高血压大鼠和血管紧张素诱导的高血压大鼠）验证我们的假设，具体目的如下：在具体目标A中，我们将纳入一项策略，以确定主动脉VSMC刚度和VSM-ECM相互作用的年龄依赖性变化，以及这些年龄诱导的变化是否与血压升高无关。在具体目标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，这项研究将导致进一步研究新的治疗策略，年龄相关的高血压，例如与药物靶向药物针对VSMC本身的水平，以减少年龄引起的主动脉僵硬，从而防止收缩压和脉压的增加在老年人。