Structural and transcriptomic alterations underlying the progression of aortic dissection in Fbn1G234D/G234D mice.

Aortic dissection (AD) is characterized by separation within the medial layers of the aortic wall. Pathogenic variants in the fibrillin-1 gene (FBN1), which cause Marfan syndrome, represent a major genetic cause of AD. In a recently established Fbn1G234D/G234D mouse model, intimomedial tears develop at 3 weeks of age, and 50% of mice die by 5 weeks from aortic rupture. Despite this severe phenotype, the magnitude and expansion of AD lesions, as well as the molecular alterations within the medial layers remain incompletely understood. In this study, we used three-dimensional propagation-based X-ray phase-contrast synchrotron imaging for reconstruction of the ascending aortas, together with single-cell RNA sequencing (scRNA-seq) analysis in Fbn1G234D/G234D mice. Synchrotron imaging revealed 1-2 elastic lamellar breaks evolved into widespread disruptions spanning the entire elastic lamellae, accompanied by localized adventitial thickening. scRNA-seq analysis followed by immunofluorescence staining showed upregulation of fibronectin (Fn1) in Fbn1G234D/G234D smooth muscle cells (SMCs). Consistently, increased FN1 expression was observed in human non-heritable AD samples. Furthermore, enhanced expression of fibronectin receptors and activation of focal adhesion kinase signaling suggested augmented extracellular matrix-SMC interactions during disease progression. These findings indicate that AD progression involves coordinated medial structural failure, adventitial remodeling, and fibronectin-associated SMC dysfunction.