title: Fibrillin-1 genetic deficiency leads to pathological ageing of arteries in mice.
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.
authors: Université Joseph Fourier, Grenoble, F-38041, France.
authors: Boubacar
authors: B
authors: Mariko
authors: Mylène
authors: M
authors: Pezet
authors: Brigitte
authors: B
authors: Escoubet
authors: Stéphanie
authors: S
authors: Bouillot
authors: Jean-Pierre
authors: JP
authors: Andrieu
authors: Barry
authors: B
authors: Starcher
authors: Daniela
authors: D
authors: Quaglino
authors: Marie-Paule
authors: MP
authors: Jacob
authors: Philippe
authors: P
authors: Huber
authors: Francesco
authors: F
authors: Ramirez
authors: Gilles
authors: G
authors: Faury
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology* / Q000502:physiology; D000818:Animals; D001011:Aorta / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D001018:Aortic Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure / Q000502:physiology; D004195:Disease Models, Animal; D000071838:Fibrillin-1; D000071837:Fibrillins; D005786:Gene Expression Regulation / Q000502:physiology; D006439:Hemodynamics; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000172:deficiency* / Q000235:genetics; D013314:Stress, Mechanical; D014463:Ultrasonography; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605724:Fbn1 protein, mouse; D054392:Adipokines