Abstract
Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition characterized by medial layer degeneration of the thoracic aorta. A thorough understanding of the regulator changes during pathogenesis is essential for medical therapy development. To delineate the cellular and molecular changes during the development of TAAD, we performed single-cell RNA sequencing of thoracic aortic cells from β-aminopropionitrile-induced TAAD mouse models at three time points that spanned from the early to the advanced stages of the disease. Comparative analyses were performed to delineate the temporal dynamics of changes in cellular composition, lineage-specific regulation, and cell–cell communications. Excessive activation of stress-responsive and Toll-like receptor signaling pathways contributed to the smooth muscle cell senescence at the early stage. Three subpopulations of aortic macrophages were identified, i.e., Lyve1+ resident-like, Cd74high antigen-presenting, and Il1rn+/Trem1+ pro-inflammatory macrophages. In both mice and humans, the pro-inflammatory macrophage subpopulation was found to represent the predominant source of most detrimental molecules. Suppression of macrophage accumulation in the aorta with Ki20227 could significantly decrease the incidence of TAAD and aortic rupture in mice. Targeting the Il1rn+/Trem1+ macrophage subpopulation via blockade of Trem1 using mLR12 could significantly decrease the aortic rupture rate in mice. We present the first comprehensive analysis of the cellular and molecular changes during the development of TAAD at single-cell resolution. Our results highlight the importance of anti-inflammation therapy in TAAD, and pinpoint the macrophage subpopulation as the predominant source of detrimental molecules for TAAD. Targeting the IL1RN+/TREM1+ macrophage subpopulation via blockade of TREM1 may represent a promising medical treatment.
Highlights
Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition occurring in ~6–10 cases every 100,000 people[1]
The aorta displayed no visible changes after 7 days of BAPN administration, which represented the early stage of pathogenesis
We provided multiple lines of evidence demonstrating the contribution of inflammation during the development of TAAD, which highlights the importance of anti-inflammation therapy in TAAD
Summary
Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition occurring in ~6–10 cases every 100,000 people[1]. In contrast with the extensive studies on abdominal aortic aneurysm and dissection (AAAD), our understanding of the pathogenesis mechanisms of TAAD remains limited, especially for sporadic TAAD, which constitutes the majority (80%) of cases[4]. Our current knowledge on the molecular mechanisms of TAAD primarily stems from genetic studies and genetic mouse models[4]. Fbn[1] mutation mouse model has been broadly used to study the molecular mechanisms of MFS-associated TAAD7–9. The knowledge obtained through genetic studies and genetic models might be limited in terms of the generalizability to a greater population of cases with sporadic TAAD. The BAPN-induced TAAD mouse model is suitable for studying the pathogenesis of mechanical stress-induced sporadic TAAD11
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