Sex- and region-specific differences in microstructural remodeling and passive biomechanics of the aorta correlate with aneurysm propensity in a mouse model of severe Marfan syndrome

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the gene that encodes fibrillin-1, a glycoprotein necessary for elastic fiber assembly and stability in the large elastic arteries. MFS is associated with aortic aneurysms that typically occur in the proximal ascending aorta and have worse outcomes in males. Mechanisms for the sex- and region-specific differences in aneurysm development and outcomes are unknown. We quantified aortic geometry, microstructural remodeling, and passive biomechanics of the thoracic ascending, thoracic descending, abdominal suprarenal, and abdominal infrarenal aorta in 4 months old male and female Fbn1^mgR/mgR (a model of severe MFS) and littermate wild-type mice to determine correlations between aortic geometry, microstructural remodeling, biomechanics, and aneurysmal dilation. We showed that aneurysmal dilation was strongly correlated with unloaded thickness, microstructural remodeling including loss of elastic fibers, deposition of collagen fibers, and decrease in cell nuclei number, and mechanical metrics including physiologic and ex vivo circumferential material stiffness. A multivariable mixed model showed that unloaded thickness, elastic fiber degradation, and ex vivo material stiffness predicted aneurysmal dilation with an adjusted R² = 0.8818. Our results highlight the potential of geometric, microstructural remodeling, and biomechanical metrics to serve as physical biomarkers for personalized aortic aneurysm diagnosis and management in MFS. STATEMENT OF SIGNIFICANCE: Marfan syndrome (MFS) is a genetic disease associated with aortic aneurysms that have distinct sex- and region-specific outcomes. The mechanisms driving these variations are unclear. We used a severe MFS mouse model (Fbn1^mgR/mgR) to explore differences in microstructural remodeling and passive wall mechanics along the aortic length in males and females. We correlated these changes with aneurysm severity, as quantified by aortic dilation. We found that sex- and region-specific alterations in unloaded thickness, microstructural remodeling, and passive mechanical properties of the aortic wall play a critical role in aortic dilation. Our findings showed that mechanical metrics, particularly ex vivo material stiffness, may serve as biomarkers for the diagnosis and management of aortic aneurysms.