Local TGF-beta sequestration by fibrillin-1 regulates vascular wall homeostasis in the thoracic aorta

Abstract Background Aortic dissection and rupture is the main cause of early cardiovascular mortality in patients with Marfan syndrome (MFS). MFS caused by a defect fibrillin-1, building block microfibrils extracellular matrix which binds transforming growth factor beta (TGF-beta) via interaction latent TGF-beta binding proteins (LTBPs). Multiple mouse models, both pharmaceutically induced genetically manipulated, have been used to investigate pathophysiology biomechanical aspects thoracic aortic aneurysms dissections. However, role has controversial, earlier studies suggesting that excess release due decreased dysfunctional fibrillin-1 leads dilation vascular damage, while other shown an important protective effect TGF-beta. Studying dedicated models for MFS, defects interfering -function may help resolve these discrepancies. Purpose This study aimed reveal insights signaling aneurysm formation MFS. Methods Mice lacking site LTBPs (Fbn1H1Δ/+ Fbn1H1Δ/H1Δ), mice truncated (Fbn1GT-8/+), combination alleles (Fbn1GT-8/ H1Δ) were subjected vivo cardiac ultrasound analysis. Ex phase-contrast synchrotron X-ray imaging was performed at Paul Scherrer Institute visualize elastic lamellae architecture wall entire excised aorta subset from each group. Results Fbn1GT-8/+, Fbn1 H1Δ/+ Fbn1H1Δ/H1Δ had normal life span, but Fbn1GT-8/ H1Δ showed increased starting 4–5 months age. The root dilated Fbn1GT-8/+ 6 age, not Fbn1H1D/+ or mice. Synchrotron images significant fragmentation mice, larger extent Surprisingly, localized elastin also found ascending despite lack formation. Moreover, displayed more severe damage. microdissections characterized alteration fiber organization, cellular influx collagen deposition, as confirmed histological Conclusions Our data suggest loss LTBP development absence aneurysm, exacerbates morphology abnormalities fibrillin-1. We therefore hypothesize local sequestration required maintain homeostasis. Funding Acknowledgement Type funding sources: Public grant(s) – National budget only. Main source(s): Foundation Cardiac Surgery (“VZW Fonds voor Hartchirurgie”), grant No. 489644Baillet-Latour Grant Medical Research