Periaortic lymphatic vessels protect against thoracic aortic dissection through mobilizing immune response

Abstract Aims Inflammation and the immune response are crucial factors in the progression of thoracic aortic dissection (TAD), while lymphatic vessels (LVs) play a key role in regulating the inflammatory response by facilitating the drainage of inflammatory mediators, and immune cell trafficking. Here, we investigated the role of LVs in the pathogenesis of TAD. Methods and results Aortas collected from TAD patients and mice both showed a reduction in the number of periaortic LVs during TAD progression. Genetic linage tracing, tissue clearing technology, and fluorochrome tracers were used to explore the draining lymph nodes (LNs) of the aorta. The results demonstrated that the tracheobronchial lymph node (TLN) was the primary draining LN for the thoracic aorta. Besides, we further found that the drainage of periaortic LVs was decreased and the immune cell population in the TLN was changed in TAD. Then, lymphatic-deficient models, including genetic ablation and TLN removal, indicated that lymphatic deficiency exacerbated TAD. Furthermore, enhancing lymphangiogenesis with hVEGF-C156S treatment inhibited TAD depended on an intact lymphatic system. Mechanistically, single-cell RNA sequencing analysis showed that lymphatic endothelial cells (LECs) recruited immune cells by CXCL12-CXCR4 signalling in TAD. Importantly, blockade of CXCR4 by AMD3100 abolished the protective role of hVEGF-C156S in TAD, revealing that periaortic LVs protected against TAD progression via CXCL12-CXCR4 signalling. Finally, single-cell RNA sequencing analysis of human TAD tissue confirmed that LEC-induced immune cell recruitment played a key role in TAD. Conclusion Our findings demonstrated that the TLN and associated periaortic LVs form a functional lymphatic system, which drains the thoracic aorta and plays an inhibitory role in TAD progression, indicating that enhancing lymphatic function may represent a potential therapeutic strategy for treating TAD.