This Program Project Grant renewal application describes studies we plan to perform as a continuation of our project on the role of vascular endothelial cells in the regulation of cardiovascular function in a variety of physiological and pathophysiological states. The project leaders represent related research disciplines, each of which will contribute to the collaborative efforts of the investigators. The common theme of the projects is the multifaceted role of the interaction among the locally released, endothelium-derived mediators, -primarily nitric oxide (NO), and oxygen free radical species -in the regulation of vascular smooth muscle functions, and parenchymal cell metabolism in heart and skeletal muscle of mice, dogs, bovine and humans. The participating investigators have been in the forefront of research in this area and it is anticipated that, as a result of the coordinated program proposed, the role of endothelial mediators in blood vessel biology as well as their possible role in the changes evoked by aging and disease states, such as heart failure, will become clearer. The overall goal of the program is to test the hypothesis that a reduction in endothelial NO synthesis and/or bioavalaibility is the dominant pathogenetic factor in the alterations of vascular and myocyte function, and cell death, as a consequence of the heart failure and aging. We plan to gain further mechanistic insight into the role of NO in these processes and to evaluate the beneficial effects of interventions directed towards the correction fo the NO deficiency by a variety of methods to reverse the aging - and heart failure - related deterioration of cellular function. Project 2 will study interactions between reactive O2 and NO-derived species in the control of signaling systems that affect coronary vessel contractile function. Project 5 will examine the pathophysiologic relevance of the reduction and restoration fo NO production on the development of heart failure. Project 6 will investigate whether the progressive increase in oxidative stress, and myocyte and cell death are characteristic of cardiac decompensation and aging. Project 4 will have as its goal to attempt to reverse vascular aging in mice by a variety of methods to reestablish control of microvascular function by NO. The Administrative Core will support the research projects. The Molecular Biology Core will coordinate all work related to the transgenic mouse colony, including the characterization of the aging vascular phenotype. Though these multidisciplinary approaches we will gain a better understanding of the causes of decompensated heart failure and the vascular consequences of aging as they relate to the synthesis and activity of endothelium - derived NO, and the attenuation or reversal of the sequelae of these conditions by enhancing the bioavailability of NO.
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