Hypertension remains as a major risk factor for a multitude of cardiovascular diseases, and as such it is responsible for significant morbidity and mortality. Recent advances in vascular biology and mechanics suggest a paradigm shift in hypertension research. It is now clear that focusing on local regulatory activities of the vascular wall that are controlled by mechanotransduction mechanisms promises significantly increased understanding. In this proposal, we will focus on the molecular mechanisms of vascular adaptation in coronary and cerebral arteries and arterioles, and the associated integrated manifestations in vessel morphology and function at the cellular and tissue levels. Toward this end, we have developed a new micro-pig model of renovascular hypertension that allows us to detail the time-course of hemodynamic changes during the development and reversal of the hypertension. Using an externally controllable suprarenal aortic coarctation model, we will delineate between purely mechanical effects and those due to engaging the renin-angiotensin system. This will allow us to explore the hypothesis that the efficacy of pharmacological therapy depends strongly on the target vascular bed and the time that the intervention is initiated during the development of the hypertension. The overall working hypothesis is that hypertension-induced alterations in cell function and matrix biology are largely due to changes in the pointwise multiaxial stress field. Specifically, we hypothesize that altered stresses (intramural and wall shear) induce (1) changes in the local expression of nitric oxide and angiotensin, (2) downregulation of potassium-sensitive ATP channels and adenosine receptor subtypes, (3) increases in RGD integrin binding sites in the matrix, similar to those in a wound healing response, and (4) spatial and temporal differences in apoptosis and the production of growth factors and proteases. These effects, balanced by a resetting of the barorecptor reflex, shear stress regulation of endothelial activity, and the myogenic response together result in the bed-specific adaptation. These hypotheses will be tested by combining clinical, molecular, cell biological, immunohistochemical, morphological, and biomechanical methods to study 5-8 vessels at multiple times during the development and reversal of hypertension in a single animal model, although there are many calls in the literature for multidisciplinary attacks on the problem of hypertension, this study will be the first to collect and synthesize such broad data. Indeed, given the vast amount of data, we suggest that combining three recently, separate theoretical developments by members of our team will enable us to develop mathematical models that synthesize the data and provide predictive capability. The latter will enable the exploration of further hypotheses in an efficient manner and guide pharmacologic delivery strategies. Years 1-2 will focus on the time-course of changes due to the development of hypertension whereas years 3-5 will focus on the time-course of changes due to reversing the hypertension either mechanically or via specific pharmacological agents, both as a function of the time during the development that the intervention is initiated. Subsequent parallel studies will focus on additional pharmacological agents and gender-related differences.
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