title: Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome.
abstract: Aortic aneurysm and dissection account for about 2% of all deaths in industrialized countries; they are also components of several genetic diseases, including Marfan syndrome (MFS). The vascular phenotype of MFS results from mutations in fibrillin-1 (FBN1), the major constituent of extracellular microfibrils. Microfibrils, either associated with or devoid of elastin, give rise to a variety of extracellular networks in elastic and non-elastic tissues. It is believed that microfibrils regulate elastic fibre formation by guiding tropo-elastin deposition during embryogenesis and early post-natal life. Hence, vascular disease in MFS is thought to result when FBN1 mutations preclude elastic fibre maturation by disrupting microfibrillar assembly. Here we report a gene-targetting experiment in mice that indicates that fibrillin-1 microfibrils are predominantly engaged in tissue homeostasis rather than elastic matrix assembly. This finding, in turn, suggests that aortic dilation is due primarily to the failure by the microfibrillar array of the adventitia to sustain physiological haemodynamic stress, and that disruption of the elastic network of the media is a secondary event.
authors.affiliation: Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: L
authors.initials: L
authors.lastname: Pereira
authors.forename: K
authors.initials: K
authors.lastname: Andrikopoulos
authors.forename: J
authors.initials: J
authors.lastname: Tian
authors.forename: S Y
authors.initials: SY
authors.lastname: Lee
authors.forename: D R
authors.initials: DR
authors.lastname: Keene
authors.forename: R
authors.initials: R
authors.lastname: Ono
authors.forename: D P
authors.initials: DP
authors.lastname: Reinhardt
authors.forename: L Y
authors.initials: LY
authors.lastname: Sakai
authors.forename: N J
authors.initials: NJ
authors.lastname: Biery
authors.forename: T
authors.initials: T
authors.lastname: Bunton
authors.forename: H C
authors.initials: HC
authors.lastname: Dietz
authors.forename: F
authors.initials: F
authors.lastname: Ramirez
mesh_terms: D000784:Aortic Dissection / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001014:Aortic Aneurysm / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D000071838:Fibrillin-1; D000071837:Fibrillins; D018390:Gene Targeting; D006801:Humans; D007150:Immunohistochemistry; D008382:Marfan Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D054392:Adipokines
chemical_list: D016326:Extracellular Matrix Proteins; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse