Smooth muscle-22α (SM22α), encoded by transgelin (TAGLN), is expressed in mesenchymal lineage cells, including myofibroblasts and smooth muscle cells. It is an F-actin binding protein that regulates the organization of actin cytoskeleton, cellular contractility and motility. SM22α is crucial for the maintenance of smooth muscle cell phenotype and its function. SM22α is also expressed in the processes of mesenchymal transition of epithelial (EMT) or endothelial cells (EndMT). The expression of TAGLN/SM22α is induced by transforming growth factor-β (TGFβ) signaling and enhanced by concomitant interleukin-1β (IL-1β) signaling. We investigated the epigenetic regulation of TAGLN expression by enhancer of zeste homolog-2 (EZH2), the methyltransferase of Polycomb, in the context of TGFβ and IL-1β signaling in endothelial cells. We demonstrate that the expression of EZH2 in endothelial cells was regulated by the inflammatory cytokine IL-1β. A decrease in both expression and activity of EZH2 led to an increase in TAGLN expression. Inhibition of EZH2 augmented TGFβ2-induced SM22α expression. The decrease of EZH2 levels in endothelial cells co-stimulated with IL-1β and TGFβ2 correlated with decreased H3K27me3 levels at the TAGLN proximal promoter. Moreover, the SM22α expression increased. Taken together, this suggests that EZH2 regulates the chromatin structure at the TAGLN promoter through tri-methylation of H3K27. EZH2 therefore acts as an epigenetic integrator of IL-1β and TGFβ2 signaling, providing an example of how cellular signaling can be resolved at the level of epigenetic regulation. Since IL-1β and TGFβ2 represent the pro-inflammatory and pro-fibrotic conditions during vascular fibroproliferative disease, we surmise that EZH2, as the molecule that integrates their signaling, could also be a promising target for development of future therapy.