MiR-21 suppresses endothelial progenitor cell proliferation by activating the TGFβ signaling pathway via downregulation of WWP1.

Endothelial damage is strongly associated with cardiovascular diseases such as atherosclerosis. Bone marrow-derived endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial homeostasis and contribute to re-endothelialization of injured vessels as well as revascularization of ischemic tissues. MicroRNAs (miRNAs) have been reported to regulate EPC biological functions. In this study, we found that EPCs of atherosclerosis patients and EPCs exposed to hypoxia have increased expression of miRNA-21 (miR-21) as well as diminished ability to proliferate. MiR-21 knockdown rescued hypoxia-induced growth arrest in EPCs. Next, we used a luciferase reporter assay to demonstrate that miR-21 downregulates the expression of WW domain-containing protein 1 (WWP1), a negative regulator of TGFβ signaling, by directly targeting the 3'-UTR of WWP1. Finally, miR-21 overexpression or WWP1 knockdown in EPCs significantly activates the TGFβ signaling pathway and inhibits cell proliferation. Taken together, our results indicate that miR-21 suppresses EPC proliferation by activating the TGFβ signaling pathway via downregulation of WWP1. These findings may help the development of strategies to enhance the vitality of EPCs for therapeutic applications.