Calpain‐2‐Mediated Endothelial Focal Adhesion Disruption in Thoracic Aortic Dissection

Thoracic aortic dissection (TAD) is a life-threatening condition with high mortality rates. Recent research suggests a potential link between early-stage TAD and endothelial barrier dysfunction, although the underlying mechanisms remain unclear. Single-cell RNA sequencing data from patients reveal that dysregulated Calpain-2 expression modulates endothelial focal adhesion proteins, serving as an early pathological hallmark and driver of TAD. Elevated plasma calpain activity is strongly associated with an increased risk of TAD and organ dysfunction. Both endogenous and exogenous calpain inhibitors effectively prevent TAD onset and progression in murine models induced by β-aminopropionitrile (BAPN). In early TAD, endothelial junction integrity in the ascending aorta and aortic arch is compromised. Endothelial-specific deletion of Capns1 mitigates early and sustained endothelial focal adhesion damage by reducing aberrant expression of Integrin alpha-V(Itgav), vinculin, and talin-1, thereby decreasing TAD incidence. In contrast, macrophage-specific Capns1 knockout does not impact TAD development but accelerates aortic dissection rupture in later stages. Mechanistically, angiotensin II upregulates Calpain-2, leading to endothelial focal adhesion activation through talin1 cleavage and Itgav assembly, thereby compromising endothelial integrity and permeability. These findings identify potential therapeutic targets for TAD prevention and treatment.