10.9 - Endothelial dysfunction drives aneurysm development in Marfan syndrome

Anna Cantalupo (Icahn School of Medicine at Mount Sinai), Keiichi Asano (Icahn School of Medicine at Mount Sinai), Jens Hansen (Icahn School of Medicine at Mount Sinai), Carmen Halabi (Washington University in St Louis), Robert Mecham (Washington University in St Louis), Ravi Iyengar (Icahn School of Medicine at Mount Sinai), Francesco Ramirez (Icahn School of Medicine at Mount Sinai)

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.

NIAMS
The Marfan Foundation