Fibrillin-1 genetic deficiency leads to pathological ageing of arteries in mice

Boubacar Mariko, Mylène Pezet, Brigitte Escoubet, Stéphanie Bouillot, Jean Pierre Andrieu, Barry Starcher, Daniela Quaglino, Marie Paule Jacob, Philippe Huber, Francesco Ramirez, Gilles Faury

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Fibrillin-1, the major component of extracellular microfibrils that associate with insoluble elastin in elastic fibres, is mainly synthesized during development and postnatal growth and is believed to guide elastogenesis. Mutations in the fibrillin-1 gene cause Marfan syndrome, a multisystem disorder characterized by aortic aneurysms and dissections. The recent finding that early deficiency of elastin modifies vascular ageing has raised the possibility that fibrillin-1 deficiency could also contribute to late-onset pathology of vascular remodelling. To address this question, we examined cardiovascular function in 3-week-old, 6-month-old, and 24-month-old mice that are heterozygous for a hypomorphic structural mutation of fibrillin-1 (Fbn1+/mgΔ mice). Our results indicate that Fbn1+/mgΔ mice, particularly those that are 24 months old, are slightly more hypotensive than wild-type littermates. Additionally, aneurysm and aortic insufficiency were more frequently observed in ageing Fbn1+/mgΔ mice than in the wild-type counterparts. We also noted substantial fragmentation and decreased number of elastic lamellae in the aortic wall of Fbn1+/mgΔ mice, which were correlated with an increase in aortic stiffness, a decrease in vasoreactivity, altered expression of elastic fibre-related genes, including fibrillin-1 and elastin, and a decrease in the relative ratio between tissue elastin and collagen. Collectively, our findings suggest that the heterozygous mgΔ mutation accelerates some aspects of vascular ageing and eventually leads to aortic manifestations resembling those of Marfan syndrome. Importantly, our data also indicate that vascular abnormalities in Fbn1 +/mgΔ mice are opposite to those induced by elastin haploinsufficiency during ageing that affect blood pressure, vascular dimensions, and number of elastic lamellae.

Original languageEnglish
Pages (from-to)33-44
Number of pages12
JournalJournal of Pathology
Volume224
Issue number1
DOIs
StatePublished - May 2011

Keywords

  • Marfan syndrome
  • aneurysm
  • arterial ageing
  • elastic lamellae
  • fibrillin-1
  • transgenic mice

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