Abstract 4361617: Recovery of Aortic Wall Structure in Mouse Models of Marfan Syndrome with Conditional Inactivation of ADAMTS6

Abstract

Background: Marfan syndrome (MFS), a complex multisystem disorder, is caused by autosomal dominant mutations in the FBN1 gene, leading to a deficiency in fibrillin-1 microfibrils, an extracellular matrix component critical for aortic wall structure and function. Recently, the ADAMTS6 gene was shown to co-localize, bind, and cleave fibrillin-1, leading to downregulation of fibrillin-1 microfibril quantity, and thus represents a potential therapeutic target for restoration of aortic wall structure, and prevention of aortic aneurysm formation. Methods: We generated a conditional smooth muscle cell deletion of Adamts6 in a known chronic MFS mouse model. Echocardiograms were completed in MFS mice with Adamts6 inactivation (“Rescue” mice), non-disease wild type controls (“WT” mice), and MFS mice. Measurements of aortic root size, outflow velocity, left ventricular end diastolic volume (LVEDV), ejection fraction (EF), and mitral E/A ratio were completed to assess cardiac phenotype. Histological sections were then created and used to further assess differences in aortic composition among groups. Results: Echocardiography revealed a statistically significant difference in aortic root diameter between WT and MFS mice (Mean difference: 0.77 mm +/- 0.16 mm, p <0.001) and between MFS and Rescue mice (Mean difference: 0.62 mm +/- 0.16 mm, p = 0.002). Pulsed-wave doppler across the aortic valve also showed significantly reduced velocity in Rescue vs. MFS mice (Mean difference: 304.4 mm/sec +/- 103.2 mm/sec). There was a significant reduction in mitral valve E wave to A wave ratio when comparing WT and MFS mice (Mean difference: 0.49 +/- 0.18, p = 0.05). Importantly, there was no significant differences in aortic root size, outflow velocity or mitral E/A ratio between WT and Rescue mice ( Figures 1 and 2 ). There were no statistical differences in LVEDV and EF among the three groups. Histologically, Rescue mice sections resembled those of WT mice, with decreased elastin breaks and proteoglycan and collagen accumulation compared to the MFS cohort ( Figure 3 ). Conclusion: Findings from this study suggest recovery of aortic wall strength and morphology in Rescue mice, consistent with the idea that Adamts6 inhibition may indeed present a possible target for MFS treatment. Ongoing work includes further quantification of aortic structure by histology and single-cell RNA sequencing of aortic tissue from across the three groups to discern changes at the cellular level.