Structural and transcriptomic alterations underlying the progression of aortic dissection in Fbn1^G234D/G234D mice

Area of Science:

• Cardiovascular Biology
• Genetics
• Biomaterials Science

Background:

• Aortic dissection (AD) is a tear in the aorta's inner layer, often linked to fibrillin-1 gene (FBN1) mutations causing Marfan syndrome.
• A specific Fbn1 mouse model exhibits severe AD phenotypes, including aortic rupture, but the underlying molecular mechanisms and lesion progression are not fully understood.

Purpose of the Study:

• To investigate the detailed structural and molecular changes in aortic dissection using a Fbn1-mutant mouse model.
• To elucidate the role of fibronectin and associated signaling pathways in AD pathogenesis.

Main Methods:

• Utilized 3D X-ray phase-contrast synchrotron imaging for high-resolution aortic reconstruction.
• Employed single-cell RNA sequencing (scRNA-seq) to analyze molecular alterations in aortic tissues.
• Performed immunofluorescence staining to validate protein expression changes.

Main Results:

• Synchrotron imaging demonstrated progression from initial elastic lamellar breaks to widespread aortic wall disruption and adventitial thickening.
• scRNA-seq identified fibronectin (Fn1) upregulation in smooth muscle cells (SMCs) of the Fbn1 mouse model.
• Increased FN1 expression was also found in human non-heritable AD samples, alongside enhanced fibronectin receptor expression and focal adhesion kinase signaling.

Conclusions:

• AD progression involves complex interplay between medial structural failure, adventitial remodeling, and fibronectin-mediated SMC dysfunction.
• Fibronectin upregulation in SMCs is a key molecular event in AD pathogenesis, potentially serving as a therapeutic target.
• This study provides novel insights into the cellular and molecular mechanisms driving aortic dissection progression.