AUTHOR=Tarraf Samar A. , de Souza Rodrigo Barbosa , Herrick Ashley , Pereira Lygia V. , Bellini Chiara 

TITLE=The Fbn1 gene variant governs passive ascending aortic mechanics in the mgΔlpn mouse model of Marfan syndrome when superimposed to perlecan haploinsufficiency

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 11 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2024.1319164

DOI=10.3389/fcvm.2024.1319164

ISSN=2297-055X

ABSTRACT=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 mg∆ lpn mice with severe Marfan syndrome phenotype advocates for exploring perlecan-encoding Hspg2 as a candidate modifier gene. To determine the effect of concurrent Hspg2 and Fbn1 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 Fbn1 gene (mg∆ lpn ), heterozygous with a mutation in the Hspg2 gene (Hspg2 +/-), and double mutants carrying both the Fbn1 and Hspg2 variants (dMut). Elastic fiber fragmentation and medial disarray progress from the internal elastic lamina outward as the ascending thoracic aorta dilates in mg∆ lpn 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 Fbn1 variant. Inherent circumferential tissue stiffening strongly correlates with the severity of aortic dilatation in mg∆ lpn and dMut mice. Perlecan haploinsufficiency superimposed to the mg∆ lpn mutation curbs the viability of dMut mice, increases the occurrence of aortic enlargement, and reduces the axial stretch in aortic tissues. Later endpoints and additional 1 Tarraf et al.structural and functional readouts are needed to uncover the mechanisms responsible for rendering dMut mice more vulnerable than mg∆ lpn mice without an Hspg2 mutation.