Transglutaminase 2 activation is involved in thoracic aortic dissection through disruption of endothelial adherens junctions.

Thoracic aortic dissection (TAD) is a life-threatening condition. While medial degeneration is a hallmark of TAD, emerging evidence underscores endothelial dysfunction as a critical initiating event. However, the specific molecular mediators orchestrating endothelial damage in TAD remain poorly defined. Transglutaminase 2 (TGM2), a multifunctional enzyme upregulated in TAD tissues, has been implicated in vascular pathology but its cell-specific roles, particularly in endothelium, are unknown. Here, we hypothesize that endothelial TGM2 is a key instigator of TAD pathogenesis. Using transmission electron microscopy in a β-aminopropionitrile (BAPN)-induced rat TAD model, we further identified profound ultrastructural damage in the aortic intima, including disrupted endothelial junctions and cell loss, etc. We found that TGM2 expression was significantly elevated specifically within the damaged aortic intima of patients and rats with TAD. In vitro, TGM2 knockdown in human aortic endothelial cells (HAECs) preserved intercellular junction integrity, whereas its overexpression exacerbated endothelial dysfunction. Mechanistically, TGM2 activation triggered the nuclear factor kappa-B (NF-κB) signaling pathway, leading to downregulation of VE-cadherin and upregulation of matrix metalloproteinase 2 (MMP2), thereby disrupting adherens junctions and promoting extracellular matrix degradation. In vivo, the TGM2 inhibitor cystamine dihydrochloride (Cys-D) attenuated aortic intima thickening, restored junctional integrity, reduced plasma TGM2 levels, and decreased TAD-related morbidity and mortality in rats. Our findings unveil a previously unrecognized endothelium-intrinsic role for TGM2 in driving TAD, positioning it as a promising therapeutic target directed at the endothelial origin of this devastating disease.