Abstract: Objective To investigate the effect of miR-17-5p on vascular lesion and expression of very low density lipoprotein receptor (VLDLR) in atherosclerotic (AS) mice. Methods ApoE-/-mice were fed with high fat diet for 15 weeks to establish atherosclerotic mice models, and these mice were injected with miR-17-5p inhibitor antagomiR-17-5p 20 mg/kg from week 13 to week 15 to interfere the expression of miR-17-5p. AS model group (injection of normal saline) and NC miRNA group (injection of negative control inhibitors) were set and C57BL/6 mice were fed with normal diet for 15 weeks as normal control group (NC group, injection of normal saline during week 13-15). HE staining was used to detect the pathological changes of arterial vessels in each group and the vascular morphological changes were measured as well, so as to investigate the therapeutic effect of interfering miR-17-5p on AS vascular lesions. According to the prediction of Targetscan target gene prediction database, VLDLR as the target gene of miR-17-5p, the distribution of VLDLR in vascular tissues of mice in each group was observed by immunofluorescence. The effect of miR-17-5p on the expression of VLDLR mRNA in the arterial tissues of each group was detected by real-time PCR, and the changes of VLDLR protein expression caused by miR-17-5p in the arterial tissues in each group was detected by Western blot. Results The results of HE staining showed that compared with the NC group, the AS model group had obvious plaques in vascular endothelium, smooth muscle cell disorder and intimal hyperplasia, while the antagomiR-17-5p treated mice had significantly less lesions compared with the NC miRNA group. The intimal area of mice in the AS model group was bigger compared with NC group, but decreased after the inhibition of miR-17-5p. There was no statistically significant difference in the area of the media in each group. Vascular lumen area was smaller and intima/media ratio (I/M) values were lower in the AS model group and the NC miRNA group compared with the NC group, while the antagomiR-17-5p group alleviated this effect (P<0.05). Immunofluorescence showed that the expression of VLDLR in the AS model group was decreased, and that in the antagomiR-17-p group was higher than that in the NC miRNA group. The expression of VLDLR gene in the AS model group was lower than that in the NC group (P<0.01), while the VLDLR gene expression was higher in the antagomiR17-p group than that in the NC miRNA group (P<0.05). The results of VLDLR expression detected by Western blot were similar. Conclusion miR-17-5p inhibitors may effectively alleviate the pathological changes of arterial vessels in AS mice by up-regulating the expression of VLDLR in arterial tissues, and may become a new therapeutic target for AS disease.