Poster No. 133 Local TGF-beta sequestration by fibrillin-1 regulates vascular wall homeostasis in the thoracic aorta

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Abstract Introduction Marfan syndrome (MFS) is caused by a defect in fibrillin-1, which binds TGF-beta via interaction with latent TGF-beta binding proteins (LTBPs). The role of TGF-beta in MFS is controversial. Objectives use dedicated mouse models for MFS, with defects interfering with TGF-beta binding and function, to gain insights into the role of TGF-beta signaling in aneurysm formation and dissection. Material & methods Mice lacking the binding site for LTBPs (Fbn1H1Δ/+ and Fbn1H1Δ/H1Δ), mice with a truncated fibrillin-1 (Fbn1GT-8/+), and mice with a combination (Fbn1GT-8/H1Δ) were subjected to cardiac ultrasound and ex vivo synchrotron X-ray imaging. Results Only Fbn1GT-8/H1Δ mice showed increased mortality (aortic rupture) starting at 4–5 months, whereas all other mice had a normal life span. Aortic root dilatation occurred both in Fbn1GT-8/+ and Fbn1GT-8/H1Δ mice at 6 months, but not in Fbn1H1D/+ or Fbn1H1Δ/H1Δ mice. Significant elastin fragmentation was observed 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 aorta of Fbn1H1Δ/+ and Fbn1H1Δ/H1Δ mice, despite a lack of aortic aneurysm formation. Moreover, Fbn1H1Δ/H1Δ mice displayed more severe aortic wall damage. Conclusion Our data suggest that loss of LTBP binding to fibrillin-1 leads to the development of localized aortic microdissections 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.

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