Marfan syndrome (MFS) is a genetic disorder caused by mutations in FBN1 , which encodes fibrillin-1, a critical component of the extracellular matrix. Mutations in FBN1 influence both the severity of aortic disease and responses to therapy, with aortic aneurysm being the leading cause of mortality in MFS patients. We generated a Marfan mouse model ( Fbn1 Q2469X/+ ) carrying the FBN1Q2467X nonsense mutation identified in patients. This mutation results in fibrillin-1 deficiency and predisposes heterozygous mice to aortic root dilation and ascending aortic aneurysm under metabolic stress, such as a high-fat diet. Homozygous Fbn1 Q2469X/Q2469X mice develop spontaneous thoracic aortic aneurysms that uniformly progress to rupture between 10 and 25 days of age, with 100% penetrance. Histopathology shows progressive vessel wall degeneration characterized by disorganized vascular smooth muscle cells, collagen loss, and elastic fiber fragmentation from early to late stages. Transcriptomic analysis identifies inflammation as the dominant process in late-stage aneurysms. Immunofluorescence assay reveals inflammatory cells prominently localized to the adventitia near rupture sites, linking adventitial inflammation to aneurysm progression. This genetically engineered Marfan model consistently develops rupture-prone aneurysms and provides a reliable, cost-effective platform for dissecting molecular mechanisms of aneurysm progression and for evaluating therapeutic strategies in Marfan syndrome and related aneurysm disorders.
Wu et al. (Thu,) studied this question.