title: Perturbations of vascular homeostasis and aortic valve abnormalities in fibulin-4 deficient mice.
abstract: The Fibulins are a 6-member protein family hypothesized to function as intermolecular bridges that stabilize the organization of extracellular matrix structures. Here, we show that reduced expression of Fibulin-4 leads to aneurysm formation, dissection of the aortic wall and cardiac abnormalities. Fibulin-4 knockdown mice with a hypomorphic expression allele arose from targeted disruption of the adjacent Mus81 endonuclease gene. Mice homozygous for the Fibulin-4 reduced expression allele (Fibulin-4(R/R)) show dilatation of the ascending aorta and a tortuous and stiffened aorta, resulting from disorganized elastic fiber networks. They display thickened aortic valvular leaflets that are associated with aortic valve stenosis and insufficiency. Strikingly, already a modest reduction in expression of Fibulin-4 in the heterozygous Fibulin-4(+/R) mice occasionally resulted in small aneurysm formation. To get insight into the underlying molecular pathways involved in aneurysm formation and response to aortic failure, we determined the aorta transcriptome of Fibulin-4(+/R) and Fibulin-4(R/R) animals and identified distinct and overlapping biological processes that were significantly overrepresented including cytoskeleton organization, cell adhesion, apoptosis and several novel gene targets. Transcriptome and protein expression analysis implicated perturbation of TGF-beta signaling in the pathogenesis of aneurysm in fibulin-4 deficient mice. Our results show that the dosage of a single gene can determine the severity of aneurysm formation and imply that disturbed TGF-beta signaling underlies multiple aneurysm phenotypes.
authors.affiliation: Department of Cell Biology and Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Hanada
authors.forename: Marcel
authors.initials: M
authors.lastname: Vermeij
authors.forename: George A
authors.initials: GA
authors.lastname: Garinis
authors.forename: Monique C
authors.initials: MC
authors.lastname: de Waard
authors.forename: Maurice G S
authors.initials: MG
authors.lastname: Kunen
authors.forename: Loretha
authors.initials: L
authors.lastname: Myers
authors.forename: Alex
authors.initials: A
authors.lastname: Maas
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Duncker
authors.forename: Carel
authors.initials: C
authors.lastname: Meijers
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
authors.forename: Roland
authors.initials: R
authors.lastname: Kanaar
authors.forename: Jeroen
authors.initials: J
authors.lastname: Essers
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D001014:Aortic Aneurysm / Q000235:genetics / Q000503:physiopathology; D001021:Aortic Valve / Q000002:abnormalities* / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D006349:Heart Valve Diseases / Q000235:genetics* / Q000503:physiopathology; D006706:Homeostasis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics
chemical_list: C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta