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

Jungsil Kim, Jesse D. Procknow, Hiromi Yanagisawa, Jessica E. Wagenseil

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Fibulin-4 is an ex-tracellular 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<sup>-/-</sup>) 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<sup>-/-</sup> and Fbln4<sup>+/+</sup> mice. Fbln4<sup>-/-</sup> AA has increased diameters compared with Fbln4<sup>+/+</sup> AA and Fbln4<sup>-/-</sup> 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<sup>-/-</sup> aortas. Fbln4<sup>-/-</sup> 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<sup>-/-</sup> aortas compared with Fbln4<sup>+/+</sup>. Additional genes in both pathways, as well as matrix metalloprotease-8 (Mmp8), are upregu-lated specifically in Fbln4<sup>-/-</sup> AA compared with Fbln4<sup>+/+</sup> AA and Fbln4<sup>-/-</sup> DA. Mmp8 is a neutrophil collagenase that targets type 1 collagen, and upregulation may be necessary to allow diameter expansion in Fbln4<sup>-/-</sup> AA. Our results provide molecular and mechanical targets for further investigation in aneurysm pathogenesis.

Original languageEnglish (US)
Pages (from-to)H103-H113
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume309
Issue number1
DOIs
StatePublished - Jul 6 2015

Fingerprint

Aortic Aneurysm
Knockout Mice
Aorta
Thoracic Aorta
Aneurysm
Thoracic Aortic Aneurysm
Elastic Tissue
Metalloproteases
Smooth Muscle Myocytes
fibulin-4
Cutis Laxa
Matrix Metalloproteinase 8
Gene Expression
Collagen Type I
Cell Wall
Compliance
Up-Regulation
Genotype
Cell Proliferation
Inflammation

Keywords

  • Aneurysm
  • Elastin
  • Fibulin-4
  • Gene array
  • Mechanics

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Differences in genetic signaling, and not mechanical properties of the wall, are linked to ascending aortic aneurysms in fibulin-4 knockout mice. / Kim, Jungsil; Procknow, Jesse D.; Yanagisawa, Hiromi; Wagenseil, Jessica E.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 309, No. 1, 06.07.2015, p. H103-H113.

Research output: Contribution to journalArticle

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abstract = "Fibulin-4 is an ex-tracellular 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 upregu-lated 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.",
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AU - Procknow, Jesse D.

AU - Yanagisawa, Hiromi

AU - Wagenseil, Jessica E.

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KW - Gene array

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