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Therapeutic angiogenesis in diabetes and hypercholesterolemia: influence of oxidative stress.

Despite significant improvements in the medical, percutaneous, and surgical management, numerous patients are first seen with non-revascularizable coronary artery disease (CAD). The growth of new blood vessels to improve myocardial perfusion (i.e., therapeutic angiogenesis) is an attractive treatment option for these patients. However, the successes of angiogenic therapy, observed in preclinical studies, have not been realized in clinical trials. Increasing evidence suggests that this discrepancy between animal and human studies may be due to the nature of the substrate, or the molecular and cellular environment within which the angiogenic agent acts. Antiangiogenic influences, including endothelial dysfunction, hypercholesterolemia, and diabetes, are present in virtually all patients with advanced CAD. Recent studies have better characterized the abnormalities associated with these disease states, providing novel targets for intervention. These substrate-modifying interventions can potentially enhance the response to protein-, gene-, or cell-based angiogenic therapy. In this review, we discuss key aspects of the angiogenic process and the pathophysiologic and molecular mechanisms that contribute to an impaired angiogenic response in the setting of endothelial dysfunction, hypercholesterolemia, and diabetes, with a focus on the role of oxidative stress. Last, we briefly explore substrate modifying agents that have been evaluated in preclinical and clinical studies to improve the angiogenic response.