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 Y. Sakai, Francesco Ramirez

Research output: Contribution to journalArticle

164 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Fibrillins 1 and 2 perform partially overlapping functions during aortic development'. Together they form a unique fingerprint.

  • Cite this

    Carta, L., Pereira, L., Arteaga-Solis, E., Lee-Arteaga, S. Y., Lenart, B., Starcher, B., Merkel, C. A., Sukoyan, M., Kerkis, A., Hazeki, N., Keene, D. R., Sakai, L. Y., & 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