Pathological mechanotransduction drives vascular smooth muscle cell phenotypic alteration in acute type A aortic dissection

Background Acute type A aortic dissection (ATAAD) is characterized by catastrophic mechanical failure of the aortic wall and remains associated with substantial mortality despite advances in surgical management. Degeneration of the aortic media and vascular smooth muscle cell (VSMC) dysfunction are consistently observed; however, the mechanisms by which altered aortic biomechanics contribute to disease progression remain poorly understood. Purpose This study aimed to determine whether pathological mechanical alterations of the aortic wall directly regulate VSMC behavior and promote progression of ATAAD. Methods Mechanical properties of human ATAAD aortic tissues and experimental mouse models were assessed using atomic force microscopy. Pharmacological activation and cell type–specific genetic deletion approaches were employed to define the role of the mechanosensitive ion channel Piezo1 in vivo. Transcriptomic profiling and chromatin accessibility analyses were performed to investigate downstream regulatory mechanisms in VSMCs. Results Human ATAAD aortas demonstrated significant extracellular matrix stiffening accompanied by increased Piezo1 expression predominantly within medial VSMCs. In vivo activation of Piezo1 accelerated aortic dilation, medial structural disruption, and mortality in BAPN-treated mice. Conversely, VSMC-specific deletion of Piezo1 markedly attenuated dissection severity and improved survival, whereas endothelial or myeloid deletion showed no measurable protective effect. At the cellular level, Piezo1 activation induced cytoskeletal remodeling and reduction of Lamin A/C, associated with altered nuclear morphology and widespread chromatin accessibility changes consistent with synthetic VSMC reprogramming. Conclusion These findings support a model in which pathological mechanical stress promotes ATAAD progression through Piezo1-dependent signaling in vascular smooth muscle cells, linking altered aortic biomechanics to nuclear remodeling and sustained cellular dysfunction. Targeting mechanically driven signaling pathways may represent a potential strategy to modify disease progression in acute aortic syndromes.