Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1.
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.
Pereira
L
L
Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
Lee
S Y
SY
Gayraud
B
B
Andrikopoulos
K
K
Shapiro
S D
SD
Bunton
T
T
Biery
N J
NJ
Dietz
H C
HC
Sakai
L Y
LY
Ramirez
F
F
D000784:Aortic Dissection / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D001011:Aorta / Q000473:pathology; D001014:Aortic Aneurysm / Q000235:genetics* / Q000473:pathology*; D000071838:Fibrillin-1; D000071837:Fibrillins; D006579:Heterozygote; D006720:Homozygote; D007738:Kyphosis / Q000235:genetics / Q000473:pathology; D008382:Marfan Syndrome / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D012272:Ribs / Q000002:abnormalities; D017540:Tunica Media / Q000473:pathology; D054392:Adipokines
D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605724:Fbn1 protein, mouse; D054392:Adipokines