Reduced Occludin expression in aortic endothelial cells mediates endothelial barrier dysfunction in aortic dissection

Area of Science:

• Cardiovascular Research
• Vascular Biology
• Molecular Medicine

Background:

• Aortic dissection (AD) is a life-threatening condition with poorly understood early mechanisms.
• Endothelial barrier dysfunction is a key feature of AD, but its molecular drivers are unclear.

Purpose of the Study:

• To investigate the role of the tight junction protein Occludin (OCLN) in the pathogenesis of aortic dissection.
• To determine if OCLN downregulation contributes to endothelial barrier dysfunction in AD.

Main Methods:

• Single-cell RNA sequencing and molecular analysis of human and mouse AD tissues.
• Generation of endothelial-specific OCLN knockout and overexpression mouse models.
• In vivo assessment of aortic pathology and survival using a β-aminopropionitrile (BAPN)-induced AD model.
• In vitro studies using human aortic endothelial cells (HAECs) to assess barrier permeability.

Main Results:

• Endothelial OCLN was significantly downregulated in human and mouse AD.
• OCLN deficiency in mice exacerbated BAPN-induced AD, increasing mortality and vascular permeability.
• OCLN overexpression preserved vascular integrity, reduced inflammation, and improved survival in AD models.
• In vitro, OCLN knockdown increased HAEC permeability, while overexpression rescued TGF-β-induced barrier dysfunction.

Conclusions:

• Endothelial Occludin downregulation is a critical initiating factor in aortic dissection.
• OCLN loss drives pathological vascular permeability and medial destruction, leading to AD.
• Targeting Occludin to preserve endothelial barrier integrity offers a potential therapeutic strategy for AD.