MicroRNA and mechanisms of impaired angiogenesis in diabetes mellitus.

Diabetes mellitus impairs physiological angiogenesis, which may be manifested as nonhealing foot ulcers or refractory angina. Multiple molecular mechanisms have been proposed. Hyperglycemia induces the generation of reactive oxygen species that cause endothelial derangements,1 including the reduced synthesis2 and accelerated degradation3 of endothelium-derived nitric oxide (NO). The bioactivity of NO is critical for angiogenic processes such as the survival, proliferation, and migration of endothelial cells.4 The impairment in NO bioactivity may also explain in part the reduced expression of a major angiogenic cytokine, vascular endothelial growth factor (VEGF), in hyperglycemic states, because NO and VEGF have a reinforcing and reciprocal relationship.5 Glucose intolerance also reduces the number and function of bone marrow–derived endothelial progenitor cells,6 circulating cells that participate in the angiogenic response. In addition to generating reactive oxygen species, hyperglycemia may impair cytoprotective mechanisms against oxidative stress. In particular, the thioredoxins play a key role in angiogenic processes by maintaining endothelial redox homeostasis, with favorable effects on protein folding, activity of reductive and metabolic enzymes, energy utilization, and transcription factor activity.7 Emerging evidence indicates that hyperglycemia upsets this cytoprotective mechanism by increasing the expression of the endogenous inhibitor thioredoxin-interacting protein (TXNIP).