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: N W M Ramnath, L J A C Hawinkels, P M van Heijningen, L te Riet, M Paauwe, M Vermeij, A H J Danser, R Kanaar, P ten Dijke, J Essers
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 16872 (Nov 26 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26607280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• EFEMP2 protein, human
• Extracellular Matrix Proteins
• Transforming Growth Factor beta1
• Transforming Growth Factor beta2

Topics

• Animals
• Aorta (cytology)
• Aorta, Thoracic (metabolism)
• Cell Proliferation
• Extracellular Matrix Proteins (deficiency, metabolism)
• Human Umbilical Vein Endothelial Cells (metabolism)
• Humans
• Mice, Inbred C57BL
• Myocytes, Smooth Muscle (metabolism)
• Real-Time Polymerase Chain Reaction
• Signal Transduction
• Transforming Growth Factor beta1 (metabolism)
• Transforming Growth Factor beta2 (blood, metabolism)