Vascular remodeling is a key process leading to arterial stenosis. Ufmylation, a novel ubiquitin-like modification, was observed to be associated with many biological processes. However, whether ufmylation is involved in the regulation of vascular remodeling remains unclear. Therefore, the present study focused on the role of ufmylation in vascular remodeling. Mouse femoral artery guidewire injury models were used for inducing vascular remodeling. We found that the expression of Ufm1 was upregulated in hyperplastic neointima. By treating vascular smooth muscle cells (VSMCs) with platelet-derived growth factor BB (PDGF-BB) for 3, 6, 12, and 24h, respectively, we observed that ufmylation was significantly activated in a time-dependent manner. Consistently, the expression levels of Ufc1, Ufl1, and Ufbp1, as key components of the ufmylation system, were all upregulated by PDGF-BB. In contrast, knockdown of Ufm1 expression attenuated PDGF-BB-induced VSMC proliferation. In addition, we observed that ufmylation was activated by lipopolysaccharide (LPS) in endothelial cells, whereas knockdown of Ufm1 was synergized with LPS-induced endothelial cell injury. These findings indicate that ufmylation may participate in regulation of the VSMC phenotypic switch and endothelial cell injury, which may help in the understanding of vascular remodeling.