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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

基本信息

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
项目类别：
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

项目摘要

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.