Recent work from our laboratory as well as that of others has established the therapeutic utility of exogenous growth factors, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2), in inducing improvements in myocardial flow and left ventricular function in a large animal model of chronic myocardial ischemia. However, clinical trials have thus far failed to demonstrate that therapeutic angiogenesis is as effective in patients as it is in normal swine and other laboratory animals. Since VEGF, FGF-2, and other angiogenic growth factors operate in large part through the release of endothelial-derived nitric oxide (NO) via the activation of tyrosine kinase receptors, the failure of effect seen in patients with coronary artery disease (CAD), hypercholesterolemia, diabetes, hypertension, and other risk factors for endothelial dysfunction may be related to a deficiency in the stimulated release of bioavaiable NO, whose production as well as that of other endothelium-derived substances is significantly altered as a result of these disease states. Reactive oxygen species (ROS) have been found to play a critical role in vascular angiogenesis. In vitro and in vivo studies have demonstrated that the angiogenic response in vascular tissue is triggered in part by ROS signaling in a highly coordinated manner. Angiogenesis is regulated by redox-sensing transcription factors such as nuclear factor kb and oxidants such as hydrogen peroxide and free radicals such as NO. These agents may act as second messengers in the pathway of the angiogenic process. Furthermore, expression of many pro-angiogenic genes such as VEGF, FGF-2, and their receptors may be regulated by redox signaling. Thus, despite the fact that ROS have been found to contribute to the detrimental effects of ischemia- reperfusion injury, and that endothelial dysfunction associated with hypercholesterolemia with increased basal oxidant stress may markedly diminish the potential of protein growth factors to induce an angiogenic effect, ROS may also contribute to the long term angiogenic response. One overarching aim of this application is to determine the role of increased oxidant stress induced by hypercholesterolemia and its modulation of the expression of these angiogenic factors. Despite this apparent dual effect of ROS in regulating the angiogenic response to ischemia reperfusion, we hypothesize that a chronic reduction in oxidant stress will have a positive impact on collateral development with a focus on the functional changes in collateral-dependent blood flow, vascular density, and microvascular regulation. However, whether this is true in a clinically relevant model of chronic myocardial ischemia will require experiments using a large animal model. To test these hypotheses we will treat chronic hypercholesterolemic pigs with anti-oxidants (vitamin E, Probucol, and resveratrol) and determine their effects on the endogenous and exogenous (VEGF and FGF) angiogenic responses to myocardium ischemia induced by narrowing the circumflex coronary artery.Clinical trials involving patients with coronary disease using angiogenic growth factors such as vascular endothelial growth factor (VEGF) or fibroblast growth factor-2 (FGF-2) or genes encoding these factors have failed to improve myocardial perfusion to a significant degree. Since hypercholesterolemia induces oxidative stress that decreases the effectiveness of angiogenic factors, we will treat hypercholesterolemic pigs with anti- oxidants (Vitamin E, Probucol, and resveratrol) and examine the changes in the molecular signaling involved in collateral development, and whether myocardial flow and left ventricular function can be improved by VEGF and FGF treatment in this model of endothelial dysfunction and increased oxidative stress. ? ? ?
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