BACKGROUND: Vascular calcification (VC) always has poor cardiovascular outcomes, but it is still difficult to control. Exosomes secreted from activated macrophages can affect VC through microRNAs (miRNAs). Research has suggested that miRNA-204 inhibits VC. We previously demonstrated that angiotensin II type 2 receptor (AT2R) plays an important role in VC; however, its underlying mechanisms are not yet clear. METHODS AND RESULTS: Rat aortic smooth muscle cells (RASMCs) and rat alveolar macrophages were cocultured with or without the phosphate and/or AT2R agonist compound 21 (C21). Calcium deposition was assessed by alizarin red staining. Protein expression was assessed by immunofluorescence staining and immunoblot analysis. The level of microRNA-204 was detected via qPCR, and its target mRNA was tested via a luciferase activity assay. C21 treatment improved the additional calcification of RASMCs cocultured with macrophages more than it did those cultured alone. The expression of miRNA-204-5p in exosomes secreted from macrophages markedly increased after C21 treatment. The decrease in the degree of calcification of RASMCs cocultured with macrophages and the expression of BMP-2, OCN, Wnt3a, β-catenin and RUNX2 induced by C21 treatment were significantly weakened after transfection with the miRNA-204-5p inhibitor. RUNX2 mRNA was the target of miRNA-204-5p in RASMCs cocultured with macrophages after C21 treatment. CONCLUSIONS: Our results suggested that miRNA-204-5p in exosomes secreted from macrophages was at least partly involved in the AT2 receptor-mediated improvement in VC induced by phosphate through targeting RUNX2 mRNA, inhibiting the Wnt/β-catenin signalling pathway and decreasing the expression of calcification-related proteins.