Inhibition of estrogen related receptor α attenuates vascular smooth muscle cell proliferation and migration by regulating RhoA/p27 Kip1 and β-Catenin/Wnt4 signaling pathway

RhoA/p27Kip1 and β-Catenin/Wnt4 signaling processes play central roles in proliferation and migration in vascular smooth muscle cells (VSMCs). ERRα, a member of orphan nuclear receptors, is a potent prognostic factor in breast, ovarian, colon and other types of tumors. However, biological significance of ERRα in VSMCs as well as the molecular mechanisms remains largely unknown. Therefore, the present study was designed to investigate whether ERRα is involved in the proliferation and migration of VSMCs in vitro and neointimal formation in vivo. The specific ERRα inverse agonist XCT790 (or ERRα shRNA) resulted in a significant inhibition of proliferation and phenotypic switch in cultured rat aortic SMCs (RASMCs). Furthermore, cycle progression, cell cycle protein transcription as well as hyperphosphorylation of the retinoblastoma protein (Rb) in RASMCs were prevented by downregulation of ERRα. Transwell assay demonstrated that migratory capacity of RASMCs was also inhibited the treatment of XCT790 (or ERRα shRNA). At the molecular levels, RhoA/p27Kip1 and β-Catenin/Wnt4 signaling pathways are involved in ERRα-mediated RASMCs growth and migration. Finally, inhibition of ERRα significantly attenuated neointimal formation in rat artery after balloon injury. These results help to further understand vascular remodeling and suggest that ERRα might be a potential target for the treatment of vascular proliferative diseases.