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 Fbn1 mice had a normal life span and displayed no overt signs of arterial disease. However, ultrastructural analyses of the ascending aorta of Fbn1 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 (Fbn1 mice). As these MFS mice also displayed aortic hypercontractility and a more abnormal aortic transcriptome, we concluded that Fbn1 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.