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

Am J Physiol Heart Circ Physiol. 2015 Jul 1;309(1):H103-13. doi: 10.1152/ajpheart.00178.2015. Epub 2015 May 1.


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.

Keywords: aneurysm; elastin; fibulin-4; gene array; mechanics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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


  • 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