Estrogen-Related Receptor γ Plays a Key Role in Vascular Calcification Through the Upregulation of BMP2 Expression.

ABSTRACT

OBJECTIVE: Vascular calcification which refers to ectopic mineralization in vascular cells is associated with several conditions, such as chronic kidney disease, atherosclerosis, and diabetes mellitus. Estrogen-related receptor (ERR)γ is a member of the orphan nuclear receptor superfamily, which plays diverse roles in regulating homeostatic and metabolic processes. However, the role of ERRγ in vascular calcification has not been investigated to date. The aim of the present study was to examine the role of ERRγ in vascular calcification. APPROACH AND RESULTS: Vascular calcification was induced by treating rat aortic vascular smooth muscle cells with calcification medium. ERRγ expression in vascular smooth muscle cells was induced during calcification medium-induced vascular calcification. Adenovirus-mediated overexpression of ERRγ in vascular smooth muscle cells resulted in the upregulation of the expression of osteogenic genes, including runt-related transcription factor 2, osteopontin, and Msx2, and the downregulation of α-smooth muscle actin. Adenovirus-mediated overexpression of ERRγ induced bone morphogenetic protein 2 (BMP2) expression, leading to increased phosphorylation of the intracellular BMP2 effector proteins SMAD1/5/8. Collectively, these data suggested that ERRγ promotes dedifferentiation of vascular smooth muscle cells to an osteogenic phenotype during the vascular calcification process. Inhibition of endogenous ERRγ expression or activity using a specific siRNA or the selective inverse agonist GSK5182 attenuated vascular calcification and osteogenic gene expression in vitro and in vivo. CONCLUSIONS: The present results indicate that ERRγ plays a key role in vascular calcification by upregulating the BMP2 signaling pathway, suggesting that inhibition of ERRγ is a potential therapeutic strategy for the prevention of vascular calcification.