Nickel exposure promotes aortic dissection progression by binding to VDAC1 and activating the cGAS-STING pathway in vascular smooth muscle cells.

This study aimed to investigate the molecular mechanism by which nickel chloride (NiCl₂) exposure promotes the progression of aortic dissection (AD), with a focus on the role of vascular smooth muscle cells (VSMCs). Through a combination of in vivo experiments using β-aminopropionitrile (BAPN)-induced AD mouse models and in vitro experiments on VSMCs, the results demonstrated that NiCl₂ exposure significantly increased the incidence of AD, enlarged the aortic diameter, and exacerbated elastic fiber damage in the aortic wall. Moreover, NiCl₂ could directly bind to the voltage-dependent anion channel 1 (VDAC1) protein on the mitochondria of VSMCs and promote its oligomerization, leading to the leakage of mitochondrial DNA (mtDNA). The leaked mtDNA activated the cGAS-STING signaling pathway in the cytoplasm, thereby inducing the phenotypic transition of VSMCs from a contractile to a synthetic state, enhancing the release of matrix metalloproteinases (MMP2, MMP9) and the expression of inflammatory factors (such as IL1β and IL6), and disrupting the structural integrity of the aortic wall. Furthermore, C-176 (a selective cGAS-STING pathway inhibitor) and STING-targeting siRNA synergistically reversed the NiCl₂-induced phenotypic transition of VSMCs, while VBIT12, an inhibitor of VDAC1, could also inhibit mtDNA leakage. This study is the first to reveal a novel mechanism by which NiCl₂ regulates VSMC dysfunction through the VDAC1-cGAS-STING axis. Our results identify NiCl2 as a synergistic co-factor that, in conjunction with pre-existing vascular fragility (the 'first hit'), significantly accelerates AD progression through this molecular 'second hit', providing new targets and a theoretical basis for the prevention and treatment of cardiovascular diseases associated with NiCl₂ exposure.