Inactivation of Fibrillin‐1 in Vascular Smooth Muscle Cells (VSMCs) but not Endothelial Cells (ECs) replicates Thoracic Aortic Aneurysm (TAA) seen in Marfan Syndrome (MFS)

Dissecting TAA in MFS is associated with elevated TGFβ activity secondary to structural or quantitative defects in FBN1 . Perinatal lethality of mice with germ line inactivation of Fbn1 has underscored the importance of fibrillin microfibrils in aortic growth and homeostasis without identifying the main tissue compartment contributing to TAA. Objective Determine the contribution of fibrillin‐1 production by VSMCs and ECs in MFS vascular pathology. Method A new conditional Fbn1 mouse model was created to allow for the selective study of fibrillin‐1 in unique tissues. Female mice with the conditional allele (Fbn1 fl ) were crossed with male transgenic mice harboring a germ line null allele (Fbn1 mgN ) and expressing Cre in either VSMCs ( SM22α‐Cre ) or ECs ( Cdh5‐Cre ). The germ line null allele was paired with the conditional allele to increase the probability of tissue specific Cre excision. Tissue specific Cre excision was monitored by crossing the tissue specific mice with RosaLacZ reporter mice. Results Inactivation of fibrillin‐1 in VSMCs (Fbn1 fl/mgN ; SM22α‐Cre + ), but not ECs, replicates the germ line null phenotype with elastic fiber fragmentation, aortic aneurysm, and death due to dissection by P16. Conclusions Lack of fibrillin‐1 production by VSMCs in the media of the ascending aorta is necessary and sufficient for the development of TAA.