Genotype-associated structural and nanomechanical alterations of aortic fibrillin-1 microfibrils in Marfan syndrome

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by mutations in the gene encoding fibrillin-1 (FBN1), the main component of extracellular microfibrils. In the aortic wall, these microfibrils maintain structural integrity and sustain hemodynamic load. Pathogenic FBN1 variants are thought to structurally and functionally impair fibrillin-1 microfibrils, leading to progressive aortic aneurysm and dissection, the major causes of morbidity and mortality in MFS. However, the molecular mechanisms whereby these genetic variants translate into structural and mechanical defects are far from being understood. Here we explored the morphology and the nanomechanical characteristics of individual aortic fibrillin-1 microfibrils from MFS patients and non-MFS controls by atomic force microscopy. The topographical assessment revealed a preserved overall pattern and periodicity of the microfibrils, but with morphological irregularities in MFS microfibril beads and interbead segments, consistent with presumed structural fragility. Force spectroscopy revealed a reduction of transverse elastic modulus in patients harboring haploinsufficient FBN1 variants. Nanoindentation analysis was indicative of localized deformation, occurring at markedly lower forces in MFS microfibril beads, suggesting diminished load-bearing capacity. These data provide direct nanoscale evidence of structural and mechanical consequences of FBN1 mutations on human aortic tissue. Altered fibrillin-1 microfibril morphology and reduced stiffness in MFS support a pathogenetic mechanism in which compromised microfibrillar integrity weakens the aortic wall, predisposing it to progressive dilation.