Fibulin-4 deficiency results in ascending aortic aneurysms

A potential link between abnormal smooth muscle cell phenotype and aneurysm progression

Jianbin Huang, Elaine C. Davis, Shelby L. Chapman, Madhusudhan Budatha, Lihua Y. Marmorstein, R. Ann Word, Hiromi Yanagisawa

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Rationale: Loss of fibulin-4 during embryogenesis results in perinatal lethality because of aneurysm rupture, and defective elastic fiber assembly has been proposed as an underlying cause for the aneurysm phenotype. However, aneurysms are never seen in mice deficient for elastin, or for fibulin-5, which absence also leads to compromised elastic fibers. Objective: We sought to determine the mechanism of aneurysm development in the absence of fibulin-4 and establish the role of fibulin-4 in aortic development. Methods And Results: We generated germline and smooth muscle cell (SMC)-specific deletion of the fibulin-4 gene in mice (Fbln4 and Fbln4, respectively). Fbln4 and Fbln4 aortic walls fail to fully differentiate, exhibiting reduced expression of SM-specific contractile genes and focal proliferation of SMCs accompanied by degenerative changes of the medial wall. Marked upregulation of extracellular signal-regulated kinase 1/2 signaling pathway was observed in the aneurysmal wall of Fbln4 and Fbln4 mice and both mutants developed aneurysm predominantly in the ascending thoracic aorta. In vitro, Fbln4 SMCs exhibit an immature SMC phenotype with a marked reduction of SM-myosin heavy chain and increased proliferative capacity. Conclusions: The vascular phenotype in Fbln4 mutant mice is remarkably similar to a subset of human thoracic aortic aneurysms caused by mutations in SMC contractile genes. Our study provides a potential link between the intrinsic properties of SMCs and aneurysm progression in vivo and supports the dual role of fibulin-4 in the formation of elastic fibers as well as terminal differentiation and maturation of SMCs in the aortic wall.

Original languageEnglish (US)
Pages (from-to)583-592
Number of pages10
JournalCirculation Research
Volume106
Issue number3
DOIs
StatePublished - Feb 2010

Fingerprint

Aortic Aneurysm
Smooth Muscle Myocytes
Aneurysm
Phenotype
Elastic Tissue
Genes
Thoracic Aortic Aneurysm
Mitogen-Activated Protein Kinase 3
Myosin Heavy Chains
Elastin
Mitogen-Activated Protein Kinase 1
Thoracic Aorta
Embryonic Development
Blood Vessels
Aorta
fibulin-4
Rupture
Up-Regulation
Mutation

Keywords

  • Aneurysms
  • ECM
  • Elastic fibers
  • Mouse
  • Smooth muscle cells

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Fibulin-4 deficiency results in ascending aortic aneurysms : A potential link between abnormal smooth muscle cell phenotype and aneurysm progression. / Huang, Jianbin; Davis, Elaine C.; Chapman, Shelby L.; Budatha, Madhusudhan; Marmorstein, Lihua Y.; Word, R. Ann; Yanagisawa, Hiromi.

In: Circulation Research, Vol. 106, No. 3, 02.2010, p. 583-592.

Research output: Contribution to journalArticle

Huang, Jianbin ; Davis, Elaine C. ; Chapman, Shelby L. ; Budatha, Madhusudhan ; Marmorstein, Lihua Y. ; Word, R. Ann ; Yanagisawa, Hiromi. / Fibulin-4 deficiency results in ascending aortic aneurysms : A potential link between abnormal smooth muscle cell phenotype and aneurysm progression. In: Circulation Research. 2010 ; Vol. 106, No. 3. pp. 583-592.
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AU - Budatha, Madhusudhan

AU - Marmorstein, Lihua Y.

AU - Word, R. Ann

AU - Yanagisawa, Hiromi

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