Fibrillins 1 and 2 perform partially overlapping functions during aortic development

Luca Carta, Lygia Pereira, Emilio Arteaga-Solis, Sui Y. Lee-Arteaga, Brett Lenart, Barry Starcher, Christian A. Merkel, Marina Sukoyan, Alexander Kerkis, Noriko Hazeki, Douglas R. Keene, Lynn Sakai, Francesco Ramirez

Research output: Contribution to journalArticle

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Abstract

Fibrillin-rich microfibrils are extracellular assemblies that impart structural properties to the connective tissue. To elucidate the contribution of fibrillin-rich microfibrils to organogenesis, we have examined the vascular phenotype of a newly created strain of mice that completely lacks fibrillin-1 and the consequences of combined deficiency of fibrillins 1 and 2 on tissue formation. The results demonstrated that fibrillins 1 and 2 perform partially overlapping functions during aortic development. Fbn1-/- mice died soon after birth from ruptured aortic aneurysm, impaired pulmonary function, and/or diaphragmatic collapse. Analysis of the neonatal Fbn1-/- aorta documented a disorganized and poorly developed medial layer but normal levels of elastin cross-links. Transcriptional profiling revealed that aneurysm progression in Fbn1 null mice is accompanied by unproductive up-regulation of gene products normally involved in tissue repair and vascular integrity, such as plasminogen activator inhibitor-1, activin A, and cysteine-rich angiogenic protein 61. In contrast to Fbn1-/- mice, Fbn2 null mice had a well developed and morphologically normal aortic wall. However, virtually all Fbn1-/-;Fbn2-/- embryos and about half of the Fbn1 -/-;Fbn2-/- embryos died in utero and displayed a significantly more severe vascular phenotype than Fbn1-/- mice. Consistent with a specialized function of fibrillin-2, electron microscopy visualized ultrastructurally different microfibrils in Fbn1 null compared with control cell cultures. Collectively, these data demonstrate that involvement of fibrillin-2 in the initial assembly of the aortic matrix overlaps in part with fibrillin-1 and that continued fibrillin-1 deposition is absolutely required for the maturation and function of the vessel during neonatal life.

Original languageEnglish (US)
Pages (from-to)8016-8023
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number12
DOIs
StatePublished - Mar 24 2006

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Microfibrils
Tissue
Blood Vessels
Angiogenic Proteins
Cysteine-Rich Protein 61
Elastin
Plasminogen Activator Inhibitor 1
Embryonic Structures
Cell culture
Electron microscopy
Cysteine
Phenotype
Structural properties
Aortic Rupture
Repair
Organogenesis
Genes
Connective Tissue
Aneurysm
Aorta

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Carta, L., Pereira, L., Arteaga-Solis, E., Lee-Arteaga, S. Y., Lenart, B., Starcher, B., ... Ramirez, F. (2006). Fibrillins 1 and 2 perform partially overlapping functions during aortic development. Journal of Biological Chemistry, 281(12), 8016-8023. https://doi.org/10.1074/jbc.M511599200

Fibrillins 1 and 2 perform partially overlapping functions during aortic development. / Carta, Luca; Pereira, Lygia; Arteaga-Solis, Emilio; Lee-Arteaga, Sui Y.; Lenart, Brett; Starcher, Barry; Merkel, Christian A.; Sukoyan, Marina; Kerkis, Alexander; Hazeki, Noriko; Keene, Douglas R.; Sakai, Lynn; Ramirez, Francesco.

In: Journal of Biological Chemistry, Vol. 281, No. 12, 24.03.2006, p. 8016-8023.

Research output: Contribution to journalArticle

Carta, L, Pereira, L, Arteaga-Solis, E, Lee-Arteaga, SY, Lenart, B, Starcher, B, Merkel, CA, Sukoyan, M, Kerkis, A, Hazeki, N, Keene, DR, Sakai, L & Ramirez, F 2006, 'Fibrillins 1 and 2 perform partially overlapping functions during aortic development', Journal of Biological Chemistry, vol. 281, no. 12, pp. 8016-8023. https://doi.org/10.1074/jbc.M511599200
Carta L, Pereira L, Arteaga-Solis E, Lee-Arteaga SY, Lenart B, Starcher B et al. Fibrillins 1 and 2 perform partially overlapping functions during aortic development. Journal of Biological Chemistry. 2006 Mar 24;281(12):8016-8023. https://doi.org/10.1074/jbc.M511599200
Carta, Luca ; Pereira, Lygia ; Arteaga-Solis, Emilio ; Lee-Arteaga, Sui Y. ; Lenart, Brett ; Starcher, Barry ; Merkel, Christian A. ; Sukoyan, Marina ; Kerkis, Alexander ; Hazeki, Noriko ; Keene, Douglas R. ; Sakai, Lynn ; Ramirez, Francesco. / Fibrillins 1 and 2 perform partially overlapping functions during aortic development. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 12. pp. 8016-8023.
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