Abstract Body: Introduction: Marfan Syndrome (MFS) is a genetic disorder that predisposes TAA with risk of dissection and rupture.
A recent clinical study revealed that the MFS aorta has significantly lower distensibility than age-matched controls for individuals less than 40 years of age but of comparable distensibility for those greater than 40 years of age, consistent with the suggestion that aortic remodeling in MFS may represent a form of early accelerated aging.
We hypothesized that growth is arrested in aged MFS mice and studied possible mechanisms by which growth is stabilized in the MFS aorta.
Methods: We contrasted biomechanics, histological, multiphoton, transcriptomic and proteomic changes in the ascending aorta of Fbn1^C1041G/+ mice against those of age-matched controls at 3, 12, and 24 months of age.
Results: biomechanical data suggested that aortic phenotype worsened in the MFS aorta from 3 months to 1 year of age, but thereafter remained relatively stable as the mouse continued to age to 2 years of age. Specifically, luminal radius of MFS aorta dilated from 895±48 at 3 months of age to 1095±62 µm (p<0.05) at 12 months of age but has not changed at 2 years of age (994±187). Aortic distensibility significantly decreased from 21.88±9.4 at 3 months of age to 9.12±3.5 mmHg^-1 at 1 year of age (p<0.01) with a non-significant change at 2 year of age. Vasoconstriction to phenylephrine and vasodilatation to acetylcholine were diminished in MFS at 1 year of age which persisted at 2 years of age. The initial increase (3 to 12 months) in mural collagen revealed by multiphoton and picrosirius red tended to also remain similar from 1 to 2 years. Given the apparent growth stabilization from 1 to 2 years, we expected to find multiple transcripts and proteins having similar expression/abundancy over this period, but this was the case for only a few. By contrast, multiple transcripts and proteins- contractile, structural ECM, matricellular, focal adhesion, proteolytic, and immune were markedly increased at 2 years relative to 1 year.
Conclusions: these data suggest a stable lesion from 1 to 2 years, thus focusing attention on possible compensatory changes in the transcriptional profile and protein abundance. It remains unclear whether the MFS aorta stabilizes independently due to temporal changes in genes secondary to the pathogenic variant in Fbn1 or if processes characteristic of natural aging counter-act potentially deleterious changes due to this pathogenic variant, or both.