Genetic analysis of the contribution of LTBP-3 to thoracic aneurysm in Marfan syndrome

Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue, caused by mutations of the microfibrillar protein fibrillin-1, that predisposes affected individuals to aortic aneurysm and rupture and is associated with increased TGF beta signaling. TGF beta is secreted from cells as a latent complex consisting of TGF beta, the TGF beta propeptide, and a molecule of latent TGF beta binding protein (LTBP). Improper extracellular localization of the latent complex can alter active TGF beta levels, and has been hypothesized as an explanation for enhanced TGF beta signaling observed in MFS. We previously reported the absence of LTBP-3 in matrices lacking fibrillin-1, suggesting that perturbed TGF beta signaling in MFS might be due to defective interaction of latent TGF beta complexes containing LTBP-3 with mutant fibrillin-1 microfibrils. To test this hypothesis, we genetically suppressed Ltbp3 expression in a mouse model of progressively severe MFS. Here, we present evidence that MFS mice lacking LTBP-3 have improved survival, essentially no aneurysms, reduced disruption and fragmentation of medial elastic fibers, and decreased Smad2/3 and Erk1/2 activation in their aortas. These data suggest that, in MFS, improper localization of latent TGF beta complexes composed of LTBP-3 and TGF beta contributes to aortic disease progression.