Abstract P105: Inducible Deletion Of Fibrillin-1 In Smooth Muscle Cells Has Modest Effects On Thoracic Aortic Dilatation In Adult Mice

Abstract

Introduction: Fibrillin-1 ( Fbn1 ) mutations are associated with thoracic aortic aneurysms (TAAs) in patients with Marfan syndrome. Constitutive deletion of Fbn1 leads to neonatal death due to aortic rupture in mice. However, the role of Fbn1 in maintaining aortic integrity during the adult phase remains unclear. Since smooth muscle cell (SMC) is a major constituent of the aortic media, this study examined whether deletion of Fbn1 in SMCs of adult mice leads to compromise of aortic integrity. Methods and Results: Fbn1 floxed mice were generated that included insertion of tdTomato as a reporter for gene deletion. Female Fbn1 floxed mice were bred with male Fbn1 floxed mice expressing CreER T2 driven by an Acta2 promotor. Tamoxifen was injected intraperitoneally for 5 days into male Fbn1 floxed littermate mice that were either Cre negative or positive (n=6-8/genotype, 5-week-old) to create sm Fbn1 +/+ and -/- mice, respectively. Gene recombination was confirmed by the presence of tdTomato in sm Fbn1 -/- mice using PCR and confocal microscopy. To investigate the impact of SMC-specific Fbn1 deletion, male sm Fbn1 +/+ and -/- littermates terminated at two intervals, 5 and 36 weeks after completion of tamoxifen injections. In situ aortic images were captured, and aortic diameters were measured at ascending, arch, and descending thoracic aortas. Five weeks after tamoxifen injection, aortic diameters of smFbn1+/+ and -/- mice were not different. Despite the long-term deletion of Fbn1 in SMCs, aortic dilatation was not observed in any regions of aortas in sm Fbn1 -/- mice compared to wild type littermates 36 weeks after tamoxifen injection. Next, we investigated whether Fbn1 deletion in SMCs augmented angiotensin II (AngII)-induced aortic dilatation. AngII was infused subcutaneously into male sm Fbn1 +/+ and -/- littermates for 12 weeks (n=11-12/genotype), started 2weeks after completion of tamoxifen injections. AngII-induced aortic dilatations were augmented modestly by SMC-specific Fbn1 deletion (+/+ 1.7±0.0, -/- 1.9±0.1 mm, P=0.047). Conclusion: Deletion of Fbn1 in SMCs did not cause spontaneous TAA formation and had modest effects on AngII-induced TAAs in adult mice. Fbn1 in SMCs does not exert a critical role in mice after the aortic structure has formed.