Biochim Biophys Acta Mol Basis Dis. 2026 Aug 14:168417. doi: 10.1016/j.bbadis.2026.168417. Online ahead of print.
ABSTRACT
Aortic dissection (AD) is a catastrophic cardiovascular emergency, yet the mechanisms underlying early endothelial barrier dysfunction in AD remain poorly understood. This study investigated the role of the tight junction protein Occludin in AD pathogenesis. Single-cell RNA sequencing of human ascending aortas, along with molecular analyses of human and mouse AD tissues, revealed a significant downregulation in endothelial Occludin. To determine causality, we generated endothelial-specific ocln knockout and adeno-associated virus-mediated overexpression mouse models and subsequently subjected them to a β-aminopropionitrile (BAPN)-induced AD model. Aortic pathologies were assessed via echocardiography, Evans blue extravasation, and histological staining, while in vitro permeability was evaluated using human aortic endothelial cells (HAECs) with fluorescein isothiocyanate-dextran. In vivo, endothelial ocln deficiency severely compromised the aortic endothelial barrier, accelerated BAPN-induced aortic dilation, and significantly exacerbated AD rupture mortality. Conversely, targeted overexpression of ocln in endothelial cells preserved vascular wall integrity, decreased vascular permeability, reduced inflammatory macrophage infiltration, mitigated elastic fiber degradation, and significantly improved survival in mice. In vitro, OCLN knockdown directly increased HAEC monolayer permeability, whereas its overexpression successfully rescued transforming growth factor-β-induced barrier dysfunction. In conclusion, our findings demonstrate that the downregulation of endothelial Occludin acts as a critical initiating factor in AD, driving pathological vascular permeability and further medial destruction. Preserving endothelial barrier integrity by targeting Occludin represents a promising novel therapeutic strategy to prevent AD progression and catastrophic rupture.
PMID:42600953 | DOI:10.1016/j.bbadis.2026.168417