Endothelial dysfunction drives aneurysm development in Marfan syndrome

Thoracic aortic aneurysm (TAA) is the major morbidity/mortality factor in Marfan syndrome (MFS), a connective tissue disease caused by mutations in fibrillin-1. We examined the impact of fibrillin-1 (Fbn1) deficiency on the integrity and function of the tunica intima by using the Cdh5-Cre transgene to selectively inactivate the Fbn1 gene in endothelial cells (ECs). The resulting Fbn1Cdh5-/- mice had a normal life span and displayed no overt signs of arterial disease. However, ultrastructural analyses of the ascending aorta of Fbn1Cdh5-/- mice at P18 and P45 revealed severe fragmentation of the internal elastic lamina (IEL) with biosynthetically active sub-endothelial cells (SMCs) breaching into the intima. Additional analyses related loss of fibrillin-1 deposition in the IEL with increased endothelial permeability, impaired EC-dependent vascular relaxation and dysregulated gene expression in mural cells. The first two abnormalities were found in common with MFS mice that are hypomorphic for fibrillin-1 throughout the entire vessel (Fbn1mgR/mgR mice). As these MFS mice also displayed aortic hypercontractility and a more abnormal aortic transcriptome, we concluded that Fbn1Cdh5-/- mice replicate the early EC-dependent events that eventually trigger full blown TAA pathology in MFS. Preliminary analyses of single cell RNASeq data indicate that loss of intimal fibrillin-1 altered the profile of aortic subclusters, particularly those corresponding to immune cells and ECs.