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NEW FINDINGS What is the central question of this study? Insulin like growth factor (IGF) 1 and its major binding protein IGFBP3 involves in collagen deregulation in several cardiovascular diseases. The role of IGFBP3 in thoracic aortic dissection and whether it regulates AoSMCs phenotypic switch have not been fully unveiled yet. What is the main finding and its importance? We demonstrate for the first time that IGFBP3 inhibits AoSMCs phenotypic switch from contractile phenotype to synthetic, decreases MMP9 activation and suppresses elastin degradation. These findings provide a better understanding of the pathogenesis of thoracic aortic dissection. IGFBP3 inhibits angiotensin II-induced aortic smooth muscle cell phenotypic switch and MMPs expression ABSTRACT: Thoracic aortic dissection (TAD) characterized by aortic media degeneration is a highly lethal disease. Aortic smooth muscle cell (AoSMC) phenotypic switch is considered a key pathophysiological change in TAD. Insulin like growth factor binding protein 3 (IGFBP3) was found to be downregulated in aortic tissues of TAD patients. The present study aimed to study the function of IGFBP3 in AoSMCs phenotypic switch and matrix metalloproteinases (MMPs) expression. We established a mouse model of TAD by Angiotensin (Ang) II infusion to BAPN-administrated mice, and found decreased IGFBP3 expression accompanied with aortic dilatation and elatin degradation in vivo. Further, mAoSMCs were isolated from mouse thoracic aorta and treated with Ang II. Ang II induced downregulation of IGFBP3 in vitro. To further study the function of IGFBP3, primary mAoSMCs were infected with adenovirus expressing IGFBP3 followed by Ang II induction. Enforced upregulation of IGFBP3 decreased MMP9 expression and activation as well as increased tissue inhibitor of metalloproteinase (TIMP) 1 expression in Ang II-induced mAoSMCs. No difference was observed in MMP2 and TIMP3 expression. IGFBP3 suppressed subsequent Ang II-induced elastin degradation in vitro. IGFBP3 inhibited Ang II-induced mAoSMCs phenotypic switch as evidenced by increased smooth muscle actin alpha 2 (ACTA2) and myosin heavy chain 11 (MYH11) expression and decreased secreted phosphoprotein 1 (SPP1) and vimentin expression. Taken together, the present study demonstrates the role of IGFBP3 in preserving AoSMCs contractile state and reducing MMP9 activation and thus promoting elastic fiber synthesis, which provides a better understanding of the pathogenesis of TAD. This article is protected by copyright. All rights reserved.