Therapeutic Angiogenesis in Diabetes and Hypercholesterolemia: Influence of Oxidative Stress

Abstract

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.

Calpain inhibition decreases myocardial apoptosis in a swine model of chronic myocardial ischemia

“…4,5 Similarly patients with metabolic syndrome have diminished angiogenic responses to chronic ischemia and alterations in a variety of mechanisms contributing to vascular bed dysfunction including the formation of collateral vessels. 6,7 We and other laboratories have reported that a major mechanism leading to vascular dysfunction in metabolic syndrome is increased oxidative stress leading to over production of reactive oxygen species (ROS) and cellular apoptosis. 7,8,9 [Figure 1]…”

Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells

“…VEGF binds and phosphorylates its receptors, leading to the activation of a variety of signaling cascades such as MAPK and Akt. Angiogenic gene therapy using plasmids encoding VEGF has been attempted in patients with coronary or peripheral artery diseases [9]. However, diabetes mellitus people often show a poor response to therapeutic angiogenesis [10].…”

Hypercholesterolemia-induced ocular disorder: Ameliorating role of phytotherapy

“…In the diabetic patient, angiogenesis was found to be associated with retinopathy [45]. In hypercholesterolemia, there was apparent decrease of myocardial vascular density and an increase of endothelial damage [46] which result from ischemia and increase of oxidative stress [47] and reduction in the expression of tissue endothelial nitric oxide synthase [48] (Fig.3).…”