Associate Provost for Research Boston University Medical Campus
NHLBI - National Heart, Lung & Blood	Research Resources

Abstract

Abstract: 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.

Thesaurus Terms:
biological signal transduction, cell biology, free radical oxygen, mitochondria, oxidative stress, phenotype, vascular endothelium
atherosclerosis, cell component structure /function, cell migration, cell proliferation, gene expression, homeostasis, nitric oxide, oxidation reduction reaction, vascular cell adhesion molecule
genetically modified animal, laboratory mouse, tissue /cell culture

Institution:	BOSTON UNIVERSITY MEDICAL CAMPUS
	715 ALBANY ST, 560
	BOSTON, MA 021182394
Fiscal Year:	2005
Department:
Project Start:	30-SEP-2005
Project End:	31-AUG-2010
ICD:	NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
IRG:	HLBP