An increase in vascular stiffness is a fundamental component of hypertension, however, little is known about mechanisms. Most prior work has focused on the extracellular matrix or endothelial control. Our Preliminary Data revealed not only that aortic vascular smooth muscle cell (VSMC) stiffness increases but also that the oscillation of elasticity changed in spontaneously hypertensive rats (SHR) compared to normotensive Wistar- Kyoto (WKY) rats. The central hypothesis of this proposal is that a significant component of the increased large artery stiffness in hypertension also is intrinsic to isolated VSMC's. The goal of this proposal is to establish that isolated VSMC stiffness increases in hypertension and to determine potential cellular/molecular mechanisms mediating these changes, which could then be investigated to uncover novel therapeutic approaches for hypertension. We will test our hypothesis in this proposal by the following strategies: First, in Specific Aim 1-1, we will determine the correlation between increased peripheral vascular resistance and increased aortic vascular stiffness during the development of systemic hypertension in SHR;Second, in Specific Aim 1-2, we will determine the alterations of VSMC stiffness and dynamic oscillation in vitro during the development of hypertension in SHR;Third, in Specific Aim 2-1, we will investigate the cellular/molecular mechanisms involved in the alteration of aortic VSMC stiffness in the development of hypertension. Finally, in Specific Aim 2-2, we will elucidate the mechanism of potential pharmaceutical targets of hypertension therapy directed at the level of the VSMC itself. One specific target, which will be studied in thi proposal, is inhibition of Rho kinase, which has already been proposed for hypertension therapy.
Hypertension is one of the most common cardiovascular diseases, which eventually results in heart or renal failure or stroke. 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 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 as hypertension develops. Once this is demonstrated, it will open up new avenues of therapy for aortic stiffness and hypertension, i.e., with pharmaceutical targets directed at the level of the VSMC itself.
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