Abstract 2013: Smooth Muscle Cell-specific Deficiency Of Fibrillin-1 Induces Aortic Aneurysms But Does Not Disrupt Elastic Fiber Formation In Mice

Background and Aim: Fibrillin-1 has a complex biology that can influence elastic fiber formation and stability. Smooth muscle cells (SMCs), the most abundant cell type of the aortic wall, synthesize and secrete fibrillin-1. The purpose of this study was to determine the effects of fibrillin-1 (FBN1) synthesis in SMCs on elastic fiber formation and aortic pathologies. Methods and Results: We generated Fbn1 floxed mice that included the insertion of tdTomato as a reporter for gene deletion. Female Fbn1 floxed mice were bred with male Fbn1 floxed mice expressing Cre transgene driven by a Tagln promotor that led to the deletion of FBN1 in SMCs (SMC-FBN1-/-). Gene recombination was confirmed by the presence of tdTomato in the aorta of SMC-FBN1-/- mice. To determine the impact of SMC-specific FBN1 deletion on aortic integrity, SMC-FBN1 +/+ and -/- littermates were either terminated at 4 weeks of age with capture of in situ and ex vivo aortic images or aortas of live animals at 8 weeks of age were monitored using ultrasound. For mice terminated at 4 weeks of age, SMC-specific FBN1 deletion resulted in increased ascending aortic length (+/+ vs -/-: 2.9 vs 3.9 mm in males, p=0.004; +/+ vs -/-: 2.9 vs 3.5 mm in females, p=0.004) and width (+/+ vs -/-: 1.5 vs 1.9 mm in males, p=0.03; +/+ vs -/-: 1.4 vs 1.7 mm in females, p=0.02) of the ascending aorta and the aortic arch (+/+ vs -/-: 1.4 vs 1.9 mm in males, p<0.001; +/+ vs -/-: 1.4 vs 1.7 mm in females, p=0.01), whereas diameters of the descending thoracic aorta and suprarenal aorta were not different between SMC-FBN1 +/+ and SMC-FBN1-/- mice in either sex. Surprisingly, elastic fibers, as determined by Verhoff staining, were present in the media of each aortic region in SMC-FBN1-/- mice at 4 weeks of age, with comparable numbers of elastic lamellae as SMC-FBN1+/+ littermates in each sex. At 8 weeks of age, ultrasound detected profound luminal dilatations of the ascending aortic region and the suprarenal abdominal region in SMC-FBN1-/- mice, compared to their wild-type littermates. Conclusion: SMC-specific deficiency of FBN1 induced aortic aneurysms progressively, increasing with age, but did not overtly affect elastic fiber formation and the number of elastic lamina layers.