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Angiotensin II (Ang II) is the predominant effector peptide of the renin–angiotensin system. Ang II contributes to vascular remodeling in many cardiovascular diseases (eg, hypertension, atherosclerosis, restenosis, and aneurysm). Orphan nuclear receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II–induced vascular remodeling. Nur77 expression was initially found to be elevated in medial vascular smooth muscle cells (VSMCs) of thoracic aortas from mice continuously infused with Ang II for 2 weeks using a subcutaneous osmotic minipump. Cellular studies revealed that Nur77 expression was upregulated by Ang II via the MAPK/PKA-CREB signaling pathway. Ang II–induced proliferation, migration, and phenotypic switching were significantly enhanced in VSMCs isolated from Nur77 −/− mice compared with wild-type VSMCs. Consistent with the role in VSMCs, we found that compared with wild-type mice, Nur77 −/− mice had elevated aortic medial areas and luminal diameters, more severe elastin disruption and collagen deposition, increased VSMC proliferation and matrix metalloproteinase production, and decreased VSMC-specific genes SM-22α and α-actin expression, after 2 weeks of exogenous Ang II administration. The results of additional experiments suggested that Nur77 suppressed Ang II–induced β-catenin signaling pathway activation by promoting β-catenin degradation and inhibiting its transcriptional activity. Our findings indicated that Nur77 is a critical negative regulator of Ang II–induced VSMC proliferation, migration, and phenotypic switching via the downregulation of β-catenin activity. Nur77 may reduce Ang II–induced vascular remodeling involved in many cardiovascular diseases.

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Background: Oxidative stress plays critical pathophysiological roles in vascular remodeling-related cardiovascular diseases, including hypertension, atherosclerosis, and restenosis. Previous studies demonstrate that SENP3, a redox-sensitive SUMO2/3-specific protease, is strongly implicated in cancer development and progression. However, the role of SENP3 in vascular remodeling remains unknown.Methods: We generated three mouse models of vascular remodeling due to low shear stress, hypertension, and atherosclerosis. The expression of SENP3 was determined by western blotting and/or immunofluorescence staining in cultured vascular smooth muscle cells (VSMCs), animal models, and human samples. The biological function of SENP3 in proliferation and migration of VSMC and vascular remodeling was further investigated in vitro and in vivo models.Findings: SENP3 was highly expressed in VSMCs of remodeled arteries, accompanied by elevated reactive oxygen species (ROS) levels. In cultured VSMCs, SENP3 protein levels were enhanced by oxidized low-density lipoprotein and Angiotensin II in a ROS-dependent manner. SENP3 overexpression significantly promoted and sh-RNA-mediated knockdown markedly inhibited VSMCs proliferation and migration. Immunofluorescence staining showed that SENP3 expression was correlated with intimal area in remodeled arteries. Furthermore, we demonstrated that SENP3 interacted with β-catenin and inhibited its proteasome-dependent degradation via de-SUMOylation of β-catenin. Most importantly, SENP3 + / − mice exhibited alleviated vascular remodeling.Interpretation: Our results highlight the important function of SENP3 as a redox sensor and mediator in vascular remodeling.