TGFβ and aortic disease severity in MFS

Background: Enhanced TGFβ signaling is observed in several heritable forms of thoracic aortic aneurysms and dissection, including Marfan syndrome (MFS). The precise role of the TGFβ signaling pathway in the disease process is currently unclear. Methods: We used a genetic approach to investigate the role of the TGFβ pathway in aortic aneurysm formation and progression by crossing the Fbn1GT-8/+ MFS mouse model with Tgfb1+/-, Tgfb2+/- and Fbn1H1D/H1D mice. The latter model is characterized by an in-frame deletion of the hybrid 1 domain of fibrillin-1, essential for binding the latent TGFβ complex in the matrix. The aortas of male compound heterozygous mice and control littermates were then studied by means of ultrasound at 6 months of age. Results: Ultrasound analyses show that compound heterozygous Fbn1GT-8/H1D and Fbn1GT-8/+;Tgfb2+/- mice present more severe aortic disease compared to Fbn1GT-8/+, Fbn1H1D/H1D, and Tgfb2+/- mice at the age of 6 months. A fraction of the Fbn1GT-8/H1D and Fbn1GT-8/+;Tgfb2+/- mice dies prematurely (as early as 4-5 months of age) due to aortic rupture. In contrast, the aortic diameters of Fbn1GT-8/+;Tgfb1+/- mice do not differ from Fbn1GT-8/+ mice at 6 months of age and the mice have a normal life span. Conclusion: These data indicate that the effect of TGFβ on aortic aneurysm formation is isoform specific and that binding of the TGFβ complex to the extracellular matrix is required for correct homeostasis in the aorta in the context of MFS