425-P: Inhibition of miR-181c Rescues Diabetes-Impaired Angiogenesis

Diabetic vascular complications are characterized by impaired angiogenic responses to ischemia, resulting in delayed healing following tissue injury. MicroRNAs (miRNAs), small non-coding RNAs that target gene expression, regulate angiogenesis in a time-dependent manner. Using a miRNA array approach, we discovered that miR-181c was regulated by angiogenic stimuli but had no previous reported role in diabetes. We sought to elucidate the role of miR-181c in diabetes-impaired angiogenesis. We found that miR-181c was inhibited in endothelial cells (ECs) exposed to hypoxia but were, conversely, elevated in high glucose. To assess the importance of miR-181c in angiogenesis, ECs were transfected with mimics or antimiRs to mimic or suppress miR-181c activity respectively. Cells with increased miR-181c activity had a reduced capacity to form tubules and lower VEGFA protein levels. Conversely, suppression of miR-181c activity augmented tubule formation and VEGFA expression. This suggests that miR-181c plays an inhibitory role in angiogenesis, at least in part, through VEGFA regulation. In vivo, miR-181c was temporally tracked following ischemic induction in the hindlimb. Early post-ischemia, when angiogenesis is important, diabetic mice had elevated miR-181c levels compared to nondiabetic controls. However, at later timepoints, miR-181c levels dropped to levels similar to nondiabetic mice. This indicates that miR-181c suppression may be critical to facilitate early responses to ischemia. Diabetic mice were injected with antimiR-181c or antimiR-Neg to determine if miR-181c knockdown rescues diabetes-impaired angiogenesis. Inhibition of miR-181c completely rescued diabetes-impaired blood flow reperfusion, restoring it back to that of nondiabetic levels. Taken together, this study has identified that miR-181c plays a key role in the regulation of angiogenesis in ischemia and in diabetes. This highlights a potential new therapeutic approach for the treatment of diabetic vascular complications.