Endothelial progenitor cells (EPCs) play a key role in repairing the injured vascular endothelium by differentiating into mature endothelial cells (ECs) or secreting cytokines in a paracrine manner to promote proliferation of existing ECs. However, the mechanisms underlying the proliferation of EPCs were not fully understood. In order to investigate the mechanisms of EPC proliferation, we isolated EPCs from mononuclear cells of mouse spleens. By manipulating E2-2 expression in vitro, we observed that E2-2 negatively regulated the proliferation of EPCs. Moreover, we noted that E2-2 negatively regulated the autophagy of EPCs by studying the expression of LC3II and p62. We also demonstrated that an autophagy inhibitor chloroquine (CQ) decreased the proliferation of EPCs in a concentration-dependent manner. Interestingly, CQ reversed the increase in cell proliferation and autophagy in the E2-2 knockdown group. Furthermore, we detected the expression of autophagy‑related protein ATG7 in EPCs which had been transfected with small interfering (siRNA)‑E2-2 and siRNA‑autophagy related 7 (ATG7) or were untransfected. Our study revealed that E2-2 regulated EPC autophagy via mediating ATG7 expression. We conclude that E2-2 inhibited EPC proliferation via suppressing their autophagy, and E2-2 regulated EPC autophagy by mediating the expression of ATG7.