MicroRNA and Mechanisms of Impaired Angiogenesis in Diabetes Mellitus

D iabetes 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 synthesis 2 and accelerated degradation 3 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). Article see p 282Is it possible that these and other disparate mechanisms for the impaired angiogenesis in diabetes mellitus have a common genomic basis?This question logically follows from the work of Caporali and colleagues in the current issue of Circulation.8 They have discovered a novel genomic mechanism for hyperglycemia-induced impairment of angiogenesis, ie, the increased expression of a specific microRNA (miRNA) that appears to orchestrate a pathophysiological response in diabetes mellitus.