The work proposed is based on the principal investigator's previous studies in connection with this ProgramProject and recent preliminary data obtained related to the progression of vascular dysfunction during theaging process. Our results allowed us to conclude that the vascular dysfunction observed with aging, ischaracterized by a progressive reduction in the synthesis and/or bioavailability of nitric oxide (NO), resultingin or caused by an increased oxidant stress in endothelial cells. Significant differences in the regulation byendothelial mediators of skeletal muscle and coronary vessel function were also found in endothelial nitricoxide synthase knockout (eNOS-KO) mice as well as type 2 diabetic (db/db) mice.
The aim of our workproposed is to evaluate to what extent the effects of aging of blood vessels is accelerated withcardiovascular disorders and whether aging of blood vessels may provide an additional risk factor foradverse cardiovascular events. These issues will be studied in two models of metabolic syndrome ofdifferent etiology, namely type 2 diabetic mice and eNOS.KO mice. In this project we plan to test thehypothesis that the effects of NADPH oxidase-derived oxidants, superoxide and hydrogen peroxide, andtheir interactions with nitric oxide, on the function of coronary and skeletal muscle resistance vessels duringthe process of aging, is the primary cause of the development of vascular dysfunction.
Specific Aim 1 is toinvestigate altered mediation of responses to dilator and constrictor agents, pressure and flow of resistancevessels with aging.
Specific Aim 2 is to study the progression of metabolic syndrome with aging. Thesestudies will involve measurements of metabolic and hormonal parameters, as well as gene expression inblood vessels during aging. Finally in Specific Aim 3 we aim to elucidate the role of reactive oxidant specieson altered regulation of blood vessels with aging, as well as localization of oxidants by state-of-the-artimaging methods. These studies will lead to a better understanding of the causes of age related vasculardysfunction and the pathogenesis of metabolic syndrome, suggesting novel therapeutic targets for theprevention or treatment of these conditions.
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