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(Circulation Research. 2007;100:738.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Perturbations of Vascular Homeostasis and Aortic Valve Abnormalities in Fibulin-4 Deficient Mice

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

From the Department of Cell Biology and Genetics (K.H., G.A.G., M.G.S.K., A.M., R.K., J.E.), Department of Pathology (M.V., C.M.), Experimental Cardiology, Thorax Centre (M.C.W., D.J.D.), Department of Radiation Oncology (R.K., J.E.), Erasmus MC, Rotterdam, The Netherlands; Howard Hughes Medical Institute and Department of Pediatrics (L.M., H.C.D.), Department of Medicine (H.C.D.), Johns Hopkins University School of Medicine, Baltimore, Md.

Correspondence to Jeroen Essers, Department of Cell Biology and Genetics, Erasmus MC, Dr Molewaterplein 50, 3015GE, Rotterdam, The Netherlands. E-mail j.essers{at}erasmusmc.nl

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-ß 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-ß signaling underlies multiple aneurysm phenotypes.

Key Words: aneurysm • aortic valve • mouse model

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