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