Document Detail

Perturbations of vascular homeostasis and aortic valve abnormalities in fibulin-4 deficient mice.
MedLine Citation:
PMID:  17293478     Owner:  NLM     Status:  MEDLINE    
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.
Katsuhiro Hanada; Marcel Vermeij; George A Garinis; Monique C de Waard; Maurice G S Kunen; Loretha Myers; Alex Maas; Dirk J Duncker; Carel Meijers; Harry C Dietz; Roland Kanaar; Jeroen Essers
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-02-09
Journal Detail:
Title:  Circulation research     Volume:  100     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-03-16     Completed Date:  2007-04-02     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  738-46     Citation Subset:  IM    
Department of Cell Biology and Genetics, Erasmus MC, Rotterdam, The Netherlands.
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MeSH Terms
Aorta, Thoracic / pathology
Aortic Aneurysm / genetics,  physiopathology
Aortic Valve / abnormalities*,  metabolism*
Extracellular Matrix Proteins / biosynthesis,  deficiency*,  genetics*
Heart Valve Diseases / genetics*,  physiopathology
Homeostasis / genetics*
Mice, Inbred C57BL
Mice, Mutant Strains
Mice, Transgenic
Signal Transduction / genetics
Transcription, Genetic
Transforming Growth Factor beta / biosynthesis,  genetics
Grant Support
Reg. No./Substance:
0/Extracellular Matrix Proteins; 0/Transforming Growth Factor beta; 0/fibulin-4
Comment In:
Circ Res. 2007 Mar 16;100(5):604-6   [PMID:  17363706 ]

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