Epigenetic processes involving long non-coding RNAs regulate endothelial gene expression. However, the underlying regulatory mechanisms causing endothelial dysfunction remain to be elucidated. Enhancer of zeste homolog 2 (EZH2) is an important rheostat of histone H3K27 trimethylation (H3K27me3) that represses endothelial targets, but EZH2 RNA binding capacity and EZH2:RNA functional interactions have not been explored in post-ischemic angiogenesis. We used formaldehyde/UV-assisted crosslinking ligation and sequencing of hybrids and identified a new role for maternally expressed gene 3 (MEG3). MEG3 formed the predominant RNA:RNA hybrid structures in endothelial cells. Moreover, MEG3:EZH2 assists recruitment onto chromatin. By EZH2-chromatin immunoprecipitation, following MEG3 depletion, we demonstrated that MEG3 controls recruitment of EZH2/H3K27me3 onto integrin subunit alpha4 (<i>ITGA4</i>) promoter. Both MEG3 knockdown or EZH2 inhibition (A-395) promoted <i>ITGA4</i> expression and improved endothelial cell migration and adhesion to fibronectin <i>in vitro</i>. The A-395 inhibitor re-directed <i>MEG3</i>-assisted chromatin remodeling, offering a direct therapeutic benefit by increasing endothelial function and resilience. This approach subsequently increased the expression of <i>ITGA4</i> in arterioles following ischemic injury in mice, thus promoting arteriogenesis. Our findings show a context-specific role for <i>MEG3</i> in guiding EZH2 to repress <i>ITGA4</i>. Novel therapeutic strategies could antagonize MEG3:EZH2 interaction for pre-clinical studies.