Changes in transmural mass transport correlate with ascending thoracic aortic aneurysm diameter in a fibulin-4 E57K knockin mouse model

Abstract

Thoracic aortic aneurysm is characterized by dilation of the aortic diameter by greater than 50%, which can lead to dissection or rupture. Common histopathology includes extracellular matrix remodeling which may affect transmural mass transport, defined as the movement of fluids and solutes across the wall. We measured in vitro ascending thoracic aorta mass transport in a mouse model with partial aneurysm phenotype penetration due to a mutation in the extracellular matrix protein fibulin-4 ( Fbln4E57K/E57K, referred to as MU-A [aneurysm] or MU-NA [non-aneurysm]). To push the aneurysm phenotype, we also included MU mice with reduced levels of lysyl oxidase ( Fbln4E57K/E57K;Lox+/-, referred to as MU-XA [extreme aneurysm]) and compared all groups to wild-type (WT) littermates. The phenotype variation allows investigation of how aneurysm severity correlates with mass transport parameters and extracellular matrix organization. We found that MU-NA ascending thoracic aortae have similar hydraulic conductance ( Lp) to WT, but 397% higher solute permeability ( ω) for 4 kDa FITC-dextran. In contrast, MU-A and MU-XA ascending thoracic aortae have 44-68% lower Lp and similar ω to WT. The results suggest that ascending thoracic aortic aneurysm progression involves an initial increase in ω, followed by a decrease in Lp after the aneurysm has formed. All MU ascending thoracic aortae are longer and have increased elastic fiber fragmentation in the extracellular matrix. There is a negative correlation between diameter and Lp or ω in MU ascending thoracic aortae. Changes in mass transport due to elastic fiber fragmentation could contribute to aneurysm progression or be leveraged for treatment.

Animal Models, Pathogenesis, and Potential Treatment of Thoracic Aortic Aneurysm

“…The mutant fibulin-4 protein is prone to dimerization and is ineffectively secreted. Homozygous Fbln4 E57K/E57K mice can survive to 1 year of age and develop large TAA at the aortic root and ascending aorta (at least 2-fold increase in diameter compared with wild-type mice) in ~50% of the mice by 7 months [106,107].…”