title: Fibulin-4 deficiency increases TGF-β signalling in aortic smooth muscle cells due to elevated TGF-β2 levels.
abstract: Fibulins are extracellular matrix proteins associated with elastic fibres. Homozygous Fibulin-4 mutations lead to life-threatening abnormalities such as aortic aneurysms. Aortic aneurysms in Fibulin-4 mutant mice were associated with upregulation of TGF-β signalling. How Fibulin-4 deficiency leads to deregulation of the TGF-β pathway is largely unknown. Isolated aortic smooth muscle cells (SMCs) from Fibulin-4 deficient mice showed reduced growth, which could be reversed by treatment with TGF-β neutralizing antibodies. In Fibulin-4 deficient SMCs increased TGF-β signalling was detected using a transcriptional reporter assay and by increased SMAD2 phosphorylation. Next, we investigated if the increased activity was due to increased levels of the three TGF-β isoforms. These data revealed slightly increased TGF-β1 and markedly increased TGF-β2 levels. Significantly increased TGF-β2 levels were also detectable in plasma from homozygous Fibulin-4(R/R) mice, not in wild type mice. TGF-β2 levels were reduced after losartan treatment, an angiotensin-II type-1 receptor blocker, known to prevent aortic aneurysm formation. In conclusion, we have shown increased TGF-β signalling in isolated SMCs from Fibulin-4 deficient mouse aortas, not only caused by increased levels of TGF-β1, but especially TGF-β2. These data provide new insights in the molecular interaction between Fibulin-4 and TGF-β pathway regulation in the pathogenesis of aortic aneurysms.
authors.affiliation: Department of Genetics, Cancer Genomics Centre Netherlands, Erasmus MC, Rotterdam, The Netherlands.|Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: N W M
authors.initials: NW
authors.lastname: Ramnath
authors.affiliation: Department of Molecular Cell Biology Leiden University Medical Centre, Leiden, The Netherlands, Cancer Genomics Centre.|Department of Gastroenterology-Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: L J A C
authors.initials: LJ
authors.lastname: Hawinkels
authors.affiliation: Department of Genetics, Cancer Genomics Centre Netherlands, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: P M
authors.initials: PM
authors.lastname: van Heijningen
authors.affiliation: Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.|Department of Pharmacology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: te Riet
authors.affiliation: Department of Molecular Cell Biology Leiden University Medical Centre, Leiden, The Netherlands, Cancer Genomics Centre.
authors.forename: M
authors.initials: M
authors.lastname: Paauwe
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Vermeij
authors.affiliation: Department of Pharmacology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: A H J
authors.initials: AH
authors.lastname: Danser
authors.affiliation: Department of Genetics, Cancer Genomics Centre Netherlands, Erasmus MC, Rotterdam, The Netherlands.|Department of Radiation Oncology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Kanaar
authors.affiliation: Department of Molecular Cell Biology Leiden University Medical Centre, Leiden, The Netherlands, Cancer Genomics Centre.
authors.forename: P
authors.initials: P
authors.lastname: ten Dijke
authors.affiliation: Department of Genetics, Cancer Genomics Centre Netherlands, Erasmus MC, Rotterdam, The Netherlands.|Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.|Department of Radiation Oncology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Essers
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology*; D001013:Aorta, Thoracic / Q000378:metabolism; D049109:Cell Proliferation; D016326:Extracellular Matrix Proteins / Q000172:deficiency* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000097:blood / Q000378:metabolism*
chemical_list: C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2