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（由适用提供）：项目摘要高血压是人类中最常见的相关慢性疾病之一，影响了全球超过10亿人。尽管几十年来进行了激烈的研究工作，但关于这种疾病的主要原因是什么，但其治疗被认为是强制性的。人们普遍认为，随着年龄的增长，血压的升高主要与正向刚度一致，但是，对机制知之甚少。大多数先前的工作都集中在细胞外基质（ECM）或内皮控制上，我们先前的研究和初步数据表明，主动脉血管平滑肌细胞（VSMC）刚度也有助于增加衰老和高血压的正向僵硬。专注于年轻高血压成年人的父母赠款提出了一个新颖的概念，即高血压的关键机制可能存在于VSMC中。在此修订应用中，我们将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，特别是区分年龄依赖性变化和主动脉VSMC机械性能的高血压依赖性变化。我们对这项修订建议的假设是，年龄引起的主动脉中VSMC和VSMC-ECM相互作用的内在刚度改变了与年轻人中HT的固有刚度不同，并且是独立的属性，是主动脉僵硬度的独立属性，并随后加速了老年人的高血压发育。该提案的目的是确定年龄引起的VSMC改变在较旧的HT发展中的重要性，并确定介导这些变化的潜在细胞/分子机制，然后可以研究这些变化以发现与年龄相关的高血压的新型预防和治疗方法。通过使用与父母赠款相同的复杂实验系统，包括整个动物，孤立的血管，重构组织和单细胞观测，我们将通过两个老年高龄大鼠模型，高血压的大鼠和血管蛋白诱导的高度诱发的大鼠，通过以下特定目的来确定策略的稳固，我们将识别A的固化范围，我们将通过两种老年高龄大鼠模型，赞助高血压大鼠和血管敏感诱导的高度诱导的大鼠来测试我们的假设。 ECM相互作用以及这些年龄是否引起的改变与血压升高无关。在特定的目标B中，我们将确定这些变化对老年动物中高血压发展的影响以及所涉及的机制。如果该假设是正确的，这项研究将导致对与年龄相关的高血压的新型治疗策略进行进一步研究，例如使用药物靶标针对VSMC本身的水平，以降低年龄诱导的主动脉僵硬，从而防止收缩压和脉搏压力较长。