The gene variant governs passive ascending aortic mechanics in the mgΔ mouse model of Marfan syndrome when superimposed to perlecan haploinsufficiency.

INTRODUCTION

Ascending thoracic aortic aneurysms arise from pathological tissue remodeling that leads to abnormal wall dilation and increases the risk of fatal dissection/rupture. Large variability in disease manifestations across family members who carry a causative genetic variant for thoracic aortic aneurysms suggests that genetic modifiers may exacerbate clinical outcomes. Decreased perlecan expression in the aorta of mgΔ mice with severe Marfan syndrome phenotype advocates for exploring perlecan-encoding as a candidate modifier gene.

METHODS

To determine the effect of concurrent and mutations on the progression of thoracic aortopathy, we characterized the microstructure and passive mechanical response of the ascending thoracic aorta in female mice of four genetic backgrounds: wild-type, heterozygous with a mutation in the gene (mgΔ), heterozygous with a mutation in the gene (), and double mutants carrying both the and variants (dMut).

RESULTS

Elastic fiber fragmentation and medial disarray progress from the internal elastic lamina outward as the ascending thoracic aorta dilates in mgΔ and dMut mice. Concurrent increase in total collagen content relative to elastin reduces energy storage capacity and cyclic distensibility of aortic tissues from mice that carry the variant. Inherent circumferential tissue stiffening strongly correlates with the severity of aortic dilatation in mgΔ and dMut mice. Perlecan haploinsufficiency superimposed to the mgΔ mutation curbs the viability of dMut mice, increases the occurrence of aortic enlargement, and reduces the axial stretch in aortic tissues.

DISCUSSION

Overall, our findings show that dMut mice are more vulnerable than mgΔ mice without an mutation, yet later endpoints and additional structural and functional readouts are needed to identify causative mechanisms.