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 Y. Sakai, Francesco Ramirez

Research output: Contribution to journalArticle

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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

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    Pereira, L., Lee, S. Y., Gayraud, B., Andrikopoulos, K., Shapiro, S. D., Bunton, T., Biery, N. J., Dietz, H. C., Sakai, L. Y., & 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