title: Phenotypic alteration of vascular smooth muscle cells precedes elastolysis in a mouse model of Marfan syndrome.
abstract: Marfan syndrome is associated with early death due to aortic aneurysm. The condition is caused by mutations in the gene (FBN1) encoding fibrillin-1, a major constituent of extracellular microfibrils. Prior observations suggested that a deficiency of microfibrils causes failure of elastic fiber assembly during late fetal development. Mice homozygous for a targeted hypomorphic allele (mgR) of Fbn1 revealed a predictable sequence of abnormalities in the vessel wall including elastic fiber calcification, excessive deposition of matrix elements, elastolysis, and intimal hyperplasia. Here we describe previously unrecognized concordant findings in elastic vessels from patients with Marfan syndrome. Furthermore, ultrastructural analysis of mgR mice revealed cellular events that initiate destructive changes. The first detectable abnormality was an unusually smooth surface of elastic laminae, manifesting the loss of cell attachments that are normally mediated by fibrillin-1. Adjacent cells adopted alteration in their expression profile accompanied by morphological changes but retained expression of vascular smooth muscle cell markers. The abnormal synthetic repertoire of these morphologically abnormal smooth muscle cells in early vascular lesions included elastin, among other matrix elements, and matrix metalloproteinase 9, a known mediator of elastolysis. Ultimately, cell processes associated with zones of elastic fiber thinning and fragmentation. These data suggest that the loss of cell attachments signals a nonproductive program to synthesize and remodel an elastic matrix. This refined understanding of the pathogenesis of vascular disease in Marfan syndrome will facilitate the development of therapeutic strategies.
authors.affiliation: Department of Comparative Medicine, Institute for Genetic Medicine, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Md, USA.
authors.forename: T E
authors.initials: TE
authors.lastname: Bunton
authors.forename: N J
authors.initials: NJ
authors.lastname: Biery
authors.forename: L
authors.initials: L
authors.lastname: Myers
authors.forename: B
authors.initials: B
authors.lastname: Gayraud
authors.forename: F
authors.initials: F
authors.lastname: Ramirez
authors.forename: H C
authors.initials: HC
authors.lastname: Dietz
mesh_terms: D000199:Actins / Q000032:analysis; D000293:Adolescent; D000328:Adult; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D004547:Elastic Tissue / Q000473:pathology*; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008382:Marfan Syndrome / Q000378:metabolism / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout; D020894:Microfibrils / Q000378:metabolism; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics; D008854:Microscopy, Electron; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014333:Tropoelastin / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000032:analysis; D054392:Adipokines
chemical_list: D000199:Actins; D000071838:Fibrillin-1; D000071837:Fibrillins; D020780:Matrix Metalloproteinase 9; D008840:Microfilament Proteins; D012333:RNA, Messenger; D014333:Tropoelastin; D014746:Vimentin; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse