Aim To verify the effects and mechanism of the deubiquitin enzyme USP22 participating in the estrogen receptor α(ERα) mediated gene transcription on vascular calcification (VC). Methods Human aortic smooth muscle cells (hASMC) were vaccinated respectively in the normal DMEM, 1.25 mmol/L CAL DMEM, 2.5 mmol/L CAL DMEM, 5 mmol/L CAL DMEM culture for 0,3, 7,9 days, with a 1%/2% Alizarin red staining, and the inverted phase contrast microscope imaging; Under the condition of 5 mmol/L CAL cultivating 0,3, 7,9 days, Western blot experiment was used to test the expression of calcification associated protein bone morphogenetic protein-2 (BMP-2), receptor activator of nuclear factor κB ligand (RANKL), cyclooxygenase-2 (COX-2), growth arrest-specific protein 6 (Gas6), ERα; Luciferase double gene report experiment was used to detect USP22 whether to participate in the ERα mediated gene transcription in hASMC; With overexpression of USP22, Western blot test was used to detect the expression of calcification associated protein BMP-2, RANKL, COX-2, Gas6, ERα. Results hASMC had significant calcium deposition at the 9th day of 1.25 mmol/L CAL condition culturing. In the condition of 2.5 mmol/L CAL and 5 mmol/L CAL culture condition, hASMC had small amount of calcium deposition at the 7th day, but at the 9th day, hASMC had obvious calcium deposition; In 5 mmol/L CAL conditions to developing, the expression of the RANKL, BMP-2, USP22 protein increased; Luciferase double gene report experimental results demonstrated that USP22 inhibited ERα mediated target gene transcription regulation; With overexpression of USP22, Western blot test demonstrated decreased expression of Gas6 protein. Conclusion With the condition of 5 mmol/L CAL concentration culture time, the model of hASMC calcification is successfully established;USP22 may inhibit ERα mediated target genes Gas6 gene transcription, and then facilitates hASMC calcification.