Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-l

Dissecting aortic aneurysm is the hallmark of Marfan syndrome (MFS) and the result of mutations in fibrillin-1, the major constituent of elastin-assoc iated extracellular microfibrils. It is yet to be established whether dysfu nction of fibrillin-1 perturbs the ability of the elastic vessel wall to su stain hemodynamic stress by disrupting microfibrillar assembly, by impairin g the homeostasis of established elastic fibers, or by a combination of bot h mechanisms, The pathogenic sequence responsible for the mechanical collap se of the elastic lamellae in the aortic wall is also unknown. Targeted mut ation of the mouse fibrillin-1 gene has recently suggested that deficiency of fibrillin-1 reduces tissue homeostasis rather than elastic fiber formati on. Here we describe another gene-targeting mutation, mgR, which shows that underexpression of fibrillin-1 similarly leads to MFS-like manifestations, Histopathological analysis of mgR/mgR specimens implicates medial calcific ation, the inflammatory-fibroproliferative response, and inflammation-media ted elastolysis in the natural history of dissecting aneurysm. More general ly, the phenotypic severity associated with various combinations of normal and mutant fibrillin-1 alleles suggests a threshold phenomenon for the func tional collapse of the vessel wall that is based on the level and the integ rity of microfibrils.