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.
Lay abstract Hypertension is one of the most common age related chronic disorder in human and is a well?established risk factor for stroke and cardiovascular diseases among older people. Less is known about mechanisms involved in the large arteries. A key feature of the current proposal is to determine the alterations occurring in aortic stiffness during aging due to the novel hypothesis, that a key component occurs intrinsic to vascular smooth muscle cells (VSMCs). By using two novel techniques, atomic force microscopy (AFM) and a reconstituted tissue model, we will identify the changes in intrinsic VSMC stiffness during aging and as hypertension develops in aged animals. Once this is demonstrated, it will open up new avenues of therapy for aortic stiffness and hypertension in elderly, i.e., with pharmaceutical targets directed at the level of the VSMC itself.
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