Enhancing Angiogenesis in Mice by VEGF-Targeting Small Activating RNAs

The prevalence of cardiovascular diseases is steadily increasing, and it is the leading cause of death worldwide. Therefore, new treatments, such as gene therapy are needed. During the last decade, the role of small noncoding RNAs (ncRNAs) in the regulation of gene expression at the transcriptional level has been shown. Promoter-targeted small RNAs recruit histone-modifying enzymes and can either repress or induce target gene expression. As an example, we have targeted mouse VEGF-A promoter with small hairpin RNAs (shRNAs) and identified two shRNAs which either repressed or induced VEGF-A expression on messenger RNA and protein level in vitro, depending on the targeted location. The changes in expression levels correlate with changes in the levels of epigenetic markers, such as histone modifications associated with repressed or active state of chromatin. In ischemic mouse hindlimbs, upregulation of VEGF-A expression increased vascularity and blood flow. When VEGF-A was upregulated in mouse myocardial infarction model, the blood vessel formation in the risk zone was observed and infarct size was significantly decreased already 2 weeks after treatment. We suggest that epigenetic upregulation of VEGF-A by ncRNAs can be transferred to clinical use for the treatment of ischemic diseases in the near future.