Differences in genetic signaling, and not mechanical properties of the wall, are linked to ascending aortic aneurysms in fibulin-4 knockout mice.

Abstract

Fibulin-4 is an extracellular matrix protein that is essential for proper assembly of arterial elastic fibers. Mutations in fibulin-4 cause cutis laxa with thoracic aortic aneurysms (TAAs). Sixty percent of TAAs occur in the ascending aorta (AA). Newborn mice lacking fibulin-4 (Fbln4(-/-)) have aneurysms in the AA, but narrowing in the descending aorta (DA), and are a unique model to investigate locational differences in aneurysm susceptibility. We measured mechanical behavior and gene expression of AA and DA segments in newborn Fbln4(-/-) and Fbln4(+/+) mice. Fbln4(-/-) AA has increased diameters compared with Fbln4(+/+) AA and Fbln4(-/-) DA at most applied pressures, confirming genotypic and locational specificity of the aneurysm phenotype. When diameter compliance and tangent modulus were calculated from the mechanical data, we found few significant differences between genotypes, suggesting that the mechanical response to incremental diameter changes is similar, despite the fragmented elastic fibers in Fbln4(-/-) aortas. Fbln4(-/-) aortas showed a trend toward increased circumferential stretch, which may be transmitted to smooth muscle cells (SMCs) in the wall. Gene expression data suggest activation of pathways for SMC proliferation and inflammation in Fbln4(-/-) aortas compared with Fbln4(+/+). Additional genes in both pathways, as well as matrix metalloprotease-8 (Mmp8), are upregulated specifically in Fbln4(-/-) AA compared with Fbln4(+/+) AA and Fbln4(-/-) DA. Mmp8 is a neutrophil collagenase that targets type 1 collagen, and upregulation may be necessary to allow diameter expansion in Fbln4(-/-) AA. Our results provide molecular and mechanical targets for further investigation in aneurysm pathogenesis.

• Authors: Jungsil Kim, Jesse D Procknow, Hiromi Yanagisawa, Jessica E Wagenseil
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 309 Issue 1 Pg. H103-13 (Jul 01 2015) ISSN: 1522-1539 [Electronic] United States
• PMID: 25934097 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 the American Physiological Society.

Chemical References

• Acute-Phase Proteins
• Adgre1 protein, mouse
• Ankrd1 protein, mouse
• Calcium-Binding Proteins
• Collagen Type VIII
• EFEMP2 protein, human
• Epiregulin
• Ereg protein, mouse
• Extracellular Matrix Proteins
• Hbegf protein, mouse
• Heparin-binding EGF-like Growth Factor
• Muscle Proteins
• Nuclear Proteins
• RNA, Messenger
• Receptors, Cell Surface
• Receptors, G-Protein-Coupled
• Repressor Proteins
• Serpina3n protein, mouse
• Serpins
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• MMP8 protein, mouse
• Matrix Metalloproteinase 8

Topics

• Acute-Phase Proteins (genetics, metabolism)
• Animals
• Animals, Newborn
• Aorta (metabolism, physiopathology, ultrastructure)
• Aorta, Thoracic (metabolism, physiopathology, ultrastructure)
• Aortic Aneurysm, Thoracic (genetics)
• Calcium-Binding Proteins
• Collagen Type VIII (genetics, metabolism)
• Cyclooxygenase 2 (genetics, metabolism)
• Elastic Modulus
• Epiregulin (genetics, metabolism)
• Extracellular Matrix Proteins (genetics)
• Gene Expression Profiling
• Heparin-binding EGF-like Growth Factor (genetics, metabolism)
• Matrix Metalloproteinase 8 (genetics, metabolism)
• Mice
• Mice, Knockout
• Microscopy, Electron
• Muscle Proteins (genetics, metabolism)
• Muscle, Smooth, Vascular (cytology, metabolism)
• Myocytes, Smooth Muscle (metabolism, ultrastructure)
• Nuclear Proteins (genetics, metabolism)
• RNA, Messenger (metabolism)
• Receptors, Cell Surface (genetics, metabolism)
• Receptors, G-Protein-Coupled
• Repressor Proteins (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Serpins (genetics, metabolism)
• Up-Regulation