Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1

Lygia Pereira, Sui Ying Lee, Barbara Gayraud, Kostantinos Andrikopoulos, Steven D. Shapiro, Tracie Bunton, Nancy Jensen Biery, Harry C. Dietz, Lynn Sakai, Francesco Ramirez

Research output: Contribution to journalArticle

346 Citations (Scopus)

Abstract

Dissecting aortic aneurysm is the hallmark of Marfan syndrome (MFS) and the result of mutations in fibrillin-1, the major constituent of elastin- associated extracellular microfibrils. It is yet to be established whether dysfunction of fibrillin-1 perturbs the ability of the elastic vessel wall to sustain hemodynamic stress by disrupting microfibrillar assembly, by impairing the homeostasis of established elastic fibers, or by a combination of both mechanisms. The pathogenic sequence responsible for the mechanical collapse of the elastic lamellae in the aortic wall is also unknown. Targeted mutation of the mouse fibrillin-1 gene has recently suggested that deficiency of fibrillin-1 reduces tissue homeostasis rather than elastic fiber formation. Here we describe another gene-targeting mutation, mgR, which shows that underexpression of fibrillin-1 similarly leads to MFS-like manifestations. Histopathological analysis of mgR/mgR specimens implicates medial calcification, the inflammatory-fibroproliferative response, and inflammation-mediated elastolysis in the natural history of dissecting aneurysm. More generally, the phenotypic severity associated with various combinations of normal and mutant fibrillin-1 alleles suggests a threshold phenomenon for the functional collapse of the vessel wall that is based on the level and the integrity of microfibrils.

Original languageEnglish (US)
Pages (from-to)3819-3823
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number7
DOIs
StatePublished - Mar 30 1999
Externally publishedYes

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Aneurysm
Microfibrils
Dissecting Aneurysm
Marfan Syndrome
Elastic Tissue
Mutation
Homeostasis
Gene Targeting
Elastin
Aortic Aneurysm
Fibrillin-1
Hemodynamics
Alleles
Inflammation
Genes

ASJC Scopus subject areas

  • General

Cite this

Pereira, L., Lee, S. Y., Gayraud, B., Andrikopoulos, K., Shapiro, S. D., Bunton, T., ... Ramirez, F. (1999). Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proceedings of the National Academy of Sciences of the United States of America, 96(7), 3819-3823. https://doi.org/10.1073/pnas.96.7.3819

Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. / Pereira, Lygia; Lee, Sui Ying; Gayraud, Barbara; Andrikopoulos, Kostantinos; Shapiro, Steven D.; Bunton, Tracie; Biery, Nancy Jensen; Dietz, Harry C.; Sakai, Lynn; Ramirez, Francesco.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 7, 30.03.1999, p. 3819-3823.

Research output: Contribution to journalArticle

Pereira, L, Lee, SY, Gayraud, B, Andrikopoulos, K, Shapiro, SD, Bunton, T, Biery, NJ, Dietz, HC, Sakai, L & Ramirez, F 1999, 'Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1', Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 7, pp. 3819-3823. https://doi.org/10.1073/pnas.96.7.3819
Pereira, Lygia ; Lee, Sui Ying ; Gayraud, Barbara ; Andrikopoulos, Kostantinos ; Shapiro, Steven D. ; Bunton, Tracie ; Biery, Nancy Jensen ; Dietz, Harry C. ; Sakai, Lynn ; Ramirez, Francesco. / Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. In: Proceedings of the National Academy of Sciences of the United States of America. 1999 ; Vol. 96, No. 7. pp. 3819-3823.
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