Reactive oxygen species (ROS) and their interactions with nitric oxide (NO) regulate a variety of signaling mechanisms that control force generation in vascular smooth muscle, endothelial cell mediator production and function, gene expression, and cellular growth and apoptosis. However, studies on vascular preparations involving stimuli which promote oxidant signaling have observed many differences in the signaling systems or functional responses regulated by ROS and NO-derived species. Our previous studies and the work of others suggest that individual ROS and reactive NO-derived species (RNS) have unique ways of either directly interacting with vascular signaling systems or regulating systems though processes influenced by redox effects caused by the metabolism of these reactive species which are expressed under specific circumstances. The current proposal focuses on developing and understanding of what processes control and determine the degree of activation and ability to influence vascular contractile function of signaling mechanisms regulated by ROS and/or RNS in isolated bovine coronary arteries that we have identified to be regulated by specific stimuli such as reoxygenation following a prolonged exposure to hypoxia, stretch and angiotensin II. A central hypothesis of the project is that the interactions between cellular redox systems controlling which ROS and NO-derived species are present and/or the expression of signaling systems they regulate have major roles in determining the degree of activation of signaling systems and the functional responses that are observed. Our studies will focus on what appear to be some of the most sensitive systems present in bovine coronary arteries that are regulated by oxidant and NO derived species, including: the vasoactive eicosanoid, oxidant and NO-derived mediators released from the endothelium, and mechanisms that control vascular smooth muscle responses linked to alterations in cGMP, MAP kinases and thiol redox and/or nitrosation.
Aim 1 examines what happens to the function of the vascular smooth muscle systems as the levels of individual ROS and RNS, and redox control mechanisms associated with cytosokic NAD (H) and NAD (P)H, glutathione and mitochondrisl redox systems are altered.
Aim 2 studies how these alterations control the regulation of force and Aim 3 investigates how changes in ROS and RNS, and redox control mechanisms alter the release of vasoactive endothelium-derived mediators. These studies will be extended through collaborations within this Program Project to other species which are likely to display alterations in NO and ROS signaling as a result of aging, the modulation of heart failure and transgenic mice lacking endothelial NO synthase (-/- eNOS) to identify how these conditions alter aspects of oxidant-NO signaling.
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