The endothelium is an important component of normal vascular homeostasis. It is known that normal? endothelial function is disturbed in the setting of atherosclerosis and its risk factors such as? hypercholesterolemia, diabetes, and hypertension. It is likely that multiple mechanisms contribute to impaired? endothelial function, however, oxidant stress in the form of reactive oxygen species (ROS) production appear? particularly important. It is also now widely appreciated that ROS act as signaling molecules that contribute to? the vascular injury response, but in atherosclerosis ROS signaling becomes dysregulated and contributes to? endothelial dysfunction. Despite this knowledge, the mechanisms of ROS signaling in the endothelium remain? obscure. This proposal is based upon the central hypothesis that mitochondria are an important? component of redox-sensitive signaling and, as a consequence, are a key determinant of endothelial? cell phenotype. The objective of this application, therefore, is to determine the role of the mitochondrion in? modulating endothelial cell phenotype and elucidate any operative mechanisms. To accomplish this goal, we? first will undertake a detailed examination of how endothelial cell phenotype modulates mitochondrial functions? such as protonmotive force (delta-muH+), mitochondrial ROS, and uncoupling protein expression. Using this? knowledge and reagents we have developed, we will then manipulate specific mitochondrial functions (delta-muH+,? UCPs) in cultured endothelial cells and determine the implications for endothelial functions known to involve? ROS, such as nitric oxide bioactivity, cell proliferation and migration, and adhesion molecule expression.? Because cells imperfectly model events in vivo, we will also manipulate mitochondrial function in vivo using? UCP-2 null mice and mice we will develop with inducible endothelial cell-specific over-expression of UCP-2.? We will then go on to determine the implications of UCP-2 manipulation endothelial phenotype in vivo both in? the resting state and in response to stress in the form of arterial injury. Successful completion of these studies? will provide mechanistic information on redox-mediated control of endothelial cell phenotype and afford us the? necessary insight to design new therapeutic strategies that focus on improving vascular homeostasis in the? setting of atherosclerosis and its risk factors.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL081587-04
Application #
7687292
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
4
Fiscal Year
2008
Total Cost
$448,177
Indirect Cost
Name
Boston University
Department
Type
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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