Abstract 41: Postnatal Deletion of Vascular Smooth Muscle Cell Transforming Growth Factor beta Receptor 2 in Mice Exacerbates Marfan-syndrome-associated Aortic Dilation

Objectives: Thoracic aortic aneurysms (TAA) are an important cause of cardiovascular death and are often part of an autosomal dominant syndrome (e.g., Marfan syndrome; MFS). The role of transforming growth factor beta (TGF-β) signaling in TAA is controversial. Excessive TGF-β signaling in aortic smooth muscle cells (SMC) is proposed to cause TAA formation; however, much data support a protective role for aortic SMC TGF-β signaling. We investigated the role of SMC TGF-β signaling in the development of MFS-associated TAA by superimposing SMC-specific deletion of Tgfbr2 on MFS-related aortic pathology of Fbn1 C1039G/+ mice. Methods: We crossed Tgfbr2 flox/flox mice with Acta2 -CreERT2 mice (Tamoxifen-inducible Cre driven by the SMC-specific Acta 2 promoter) to generate mice with inducible deletion of Tgfbr 2 in SMCs. 4 groups of mice were studied: 1) Fbn1 +/+ , Acta2 -CreERT2 o/o , Tgfbr2 flox/flox mice received Tamoxifen (wild-type control); 2) Fbn1 C1039G /+ , Acta2 -CreERT2 o/o , Tgfbr2 flox/flox mice received Tamoxifen (MFS; controlled for Tamoxifen); 3) Fbn1 C1039G /+ , Acta2 -CreERT2 +/o , Tgfbr2 flox/flox mice received vehicle (MFS; controlled for Acta2 -CreERT2 +/o ); 4) Fbn1 C1039G /+ , Acta2 -CreERT2 +/o , Tgfbr2 flox/flox mice received Tamoxifen (SMC- Tgfbr2 -/- superimposed on MFS). All mice received Tamoxifen or vehicle at 6 wk of age; ascending aortic anatomy was assessed at 16 wk of age. Results: Compared to wild-type mice, both groups of MFS mice had significantly increased ascending aortic diameter (~30%; p<0.05; ANOVA). Both groups of mice with MFS alone (Tamoxifen- and Acta2 -CreERT2 +/o -controls) showed comparable ascending aorta dilation and similar prevalence of aortic intramural hematoma. Superimposing the SMC- Tgfbr2 -/- genotype on the Fbn1 C1039G /+ genotype mice further increased both ascending aorta diameter (>40%; p<0.05; ANOVA) and intramural hematoma rate (~4-fold; p<0.05, X ° test) compared to mice with MFS alone. Studies are under way to delineate the alterations of vascular SMC TGF-β signaling in these models. Conclusions: Our data suggest that loss of TGF-β signaling in vascular SMC exacerbates aortic pathology in MFS mice and that vascular SMC TGF-β signaling protects against TAA formation induced by fibrillin deficiency.