Mitochondrial Modulation of Endothelial Phenotype

Boston University Medical Campus, Boston MA

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Abstract

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