Age- and sex-specific biomechanics and extracellular matrix remodeling of the ascending aorta in a mouse model of severe Marfan Syndrome.

Thoracic aortic aneurysm (TAA) is associated with Marfan syndrome (MFS), a connective tissue disorder caused by mutations in fibrillin-1. Sexual dimorphism has been recorded for TAA outcomes in MFS, but detailed studies on the differences in TAA progression in males and females and their relationships to outcomes have not been performed. The aims of this study were to determine sex differences in the diameter dilatation, mechanical properties, and extracellular matrix (ECM) remodeling over time in a severe mouse model (Fbn1mgR/mgR = MU) of MFS-associated TAA that has a shortened lifespan. Male and female MU and wildtype (WT) mice were used at 1-4 months of age. Blood pressure and in vivo diameters of the ascending thoracic aorta were recorded using a tail cuff system and ultrasound imaging, respectively. Ex vivo mechanics and ECM remodeling of the aorta were characterized using a biaxial test system and multiphoton imaging, respectively. We showed that mechanical properties, such as structural and material stiffness, and ECM remodeling, such as elastic and collagen fiber content, correlated with diameter dilatation during TAA progression. Male MU mice had accelerated rates of diameter dilatation, stiffening, and ECM remodeling compared to female MU mice that may have contributed to their decreased lifespan. The correlation of mechanical properties and ECM remodeling with diameter dilatation suggest that they may be useful biomarkers for TAA progression. The differences in diameter dilatation and lifespans in male and female MU mice indicate that sex is an important consideration for managing thoracic aortic aneurysm in MFS.

Increases in hydraulic conductance and solute permeability in a mouse model of ascending thoracic aortic aneurysm.

Large elastic arteries, such as the aorta, contain concentric layers of elastic laminae composed mainly of the extracellular matrix protein elastin. The structure of the elastic laminae could affect transmural mass transport and contribute to aortic disease progression. We studied the effects of a genetic mutation (LoxM292R/+, referred to as MU) in mice associated with ascending thoracic aortic aneurysm (TAA) on the mass transport and elastic laminae structure. Solute absent fluid flux and hydraulic conductance through the ascending aortic wall were not significantly different between groups, however solute present fluid flux, hydraulic conductance, solute flux, and solute permeability of 4 kDa FITC-dextran were significantly increased in the MU group, indicating that movement of small molecules into the aortic wall is facilitated in MU mice. Quantification from light microscopy images of the ascending aorta showed no significant differences in wall thickness, or inner elastic lamina fenestration size and density, but an increase in the number of elastic laminae breaks in the MU group. Ultrastructural comparisons from transmission electron micrographs suggest less dense and disorganized elastic laminae in MU aorta that may also contribute to the transport differences. Our results provide an initial investigation into the connections between mass transport and elastic laminae structure, specifically in a genetic mouse aneurysm model, which can be further used to understand TAA pathology and develop treatment strategies.