Aneurysms develop as a consequence of the abnormal remodeling of the vessel wall extracellular matrix. Nitric oxide (NO) is believed to be a major determinant of vessel wall architecture in response to hemodynamic stimuli, serving as a mediator in vascular wall remodeling. In a number of pathologic states, diminished bioavailable NO has been shown to Cause vessel wall dysfunction. Yet to date, the mechanisms by which derangements in local NO concentration lead to abnormal vessel wall remodeling remain undefined. We hypothesize that NO dysregulation, similar to that known to occur in atherosclerotic states, is associated with pathologic vessel wall remodeling by increasing the expression of matrix metalloproteinases (MMPs), a family of enzymes known to degrade elastin and collagen. It is speculated that this pathologic remodeling is the basis for aortic aneurysm formation. In the present proposal, novel approaches will be used to examine the role of the nitric oxide synthase (NOS)-derived free radical, NO, on MMP-dependent vessel wall remodeling. Given recent evidence that MMP-9 (alternatively known as the 92 kD gelatinase or gelatinase B) plays a key role in aneurysm development in vivo, special emphasis will be placed on interactions between NO and this MMP family member (Specific Aim 1).
In Specific Aim II, in vitro cell culture models will be employed to determine biochemical and molecular interactions between NO and various MMPs generated by smooth muscle cells and macrophages. The findings in the in vitro cell culture model will serve as the basis for experiments in Specific Aim III using aortic explants, which will allow us to further define the physiologic relevance of these interactions ex vivo. Finally, in Specific Aim III, the role of the NO-MMP axis on aneurysm development will be tested in an in vivo aortic aneurysm model. Understanding of the role of NO and MMPs in vessel wall remodeling could be of major clinical importance from a therapeutic perspective. The results of these studies will set the stage for future in vivo clinical studies examining the effects of NO manipulation on MMP expression. Understanding the role of NO in regulating MMP-dependent tissue remodeling will enable us to target molecular events that underlie aneurysm formation and should be important in assisting the development of therapeutic strategies to prevent vessel wall destruction.
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