The fibrillin-1 hypomorphic mgR/mgR murine model of Marfan syndrome shows severe elastolysis in all segments of the aorta

Schwill, Simon; Seppelt, Philipp; Grünhagen, Johannes; Ott, Claus‐Eric; Jugold, Manfred; Ruhparwar, Arjang; Robinson, Peter N.; Kretzler, Matthias; Kallenbach, Klaus

doi:10.1016/j.jvs.2012.10.007

Cited by 40 publications

(49 citation statements)

References 25 publications

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“…Collectively, these observations suggest that increased material stiffness, if high enough, can contribute to the development of an aneurysm, not merely be a consequence of aneurysmal dilatation. Finally, this observed regional difference in aortic mechanics is consistent with findings that elastic fibers are fragmented throughout the aorta in the mgR/mgR mouse, though most so in the ATA (Schwill et al, 2013). We emphasize, therefore, that the ATA, not DTA, is particularly susceptible to aneurysmal dilation and mechanical failure by dissection/rupture in mice and humans.…”

Section: Discussionsupporting

confidence: 87%

Differential ascending and descending aortic mechanics parallel aneurysmal propensity in a mouse model of Marfan syndrome

Bellini

Korneva

Zilberberg

et al. 2016

Journal of Biomechanics

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Marfan syndrome (MFS) is a multi-system connective tissue disorder that results from mutations to the gene that codes the elastin-associated glycoprotein fibrillin-1. Although elastic fibers are compromised throughout the arterial tree, the most severe phenotype manifests in the ascending aorta. By comparing biaxial mechanics of the ascending and descending thoracic aorta in a mouse model of MFS, we show that aneurysmal propensity correlates well with both a marked increase in circumferential material stiffness and an increase in intramural shear stress despite a near maintenance of circumferential stress. This finding is corroborated via a comparison of the present results with previously reported findings for both the carotid artery from the same mouse model of MFS and for the thoracic aorta from another model of elastin-associated glycoprotein deficiency that does not predispose to thoracic aortic aneurysms. We submit that the unique biaxial loading of the ascending thoracic aorta conspires with fibrillin-1 deficiency to render this aortic segment vulnerable to aneurysm and rupture.

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Section: Discussionsupporting

confidence: 87%

Differential ascending and descending aortic mechanics parallel aneurysmal propensity in a mouse model of Marfan syndrome

Bellini

Korneva

Zilberberg

et al. 2016

Journal of Biomechanics

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“…Additionally, no significant gene expression differences were found when tissue from normal and diseased aortic regions were compared from the same TAA patient (9,58), so these studies do not give information about why aneurysms develop in specific vascular locations. Schwill et al (69) investigated changes in aortic gene expression for a Marfan mouse model (mgR) and found increases in inflammatory pathway genes, consistent with our results. However, they pooled thoracic and abdominal aortic samples so locational differences in gene expression cannot be compared.…”

Section: Regulated In Fbln4supporting

confidence: 90%

Differences in genetic signaling, and not mechanical properties of the wall, are linked to ascending aortic aneurysms in fibulin-4 knockout mice

Kim

Procknow

Yanagisawa

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…In the present study, we extended this observation to ASMCs isolated from Wt and Fbn1 mgR/mgR mice (18,20). Fbn1 mgR/mgR mice represent a murine model that replicates the clinically severe and progressive form of human MFS, with death from aortic dissection and rupture during the first year of life accompanied by enhanced TGFβ signaling in the media of the thoracic aorta (19,25).…”

Section: Discussionmentioning

confidence: 66%

“…In the present study, we present data that identify LTBP-3 as an important contributor to TAA in MFS. (19,20). The mutant allele encodes a WT protein, but the animals produce only 10-20% of the normal amount of fibrillin-1 (19).…”

mentioning

confidence: 99%

Genetic analysis of the contribution of LTBP-3 to thoracic aneurysm in Marfan syndrome

Zilberberg

Phoon

Robertson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue, caused by mutations of the microfibrillar protein fibrillin-1, that predisposes affected individuals to aortic aneurysm and rupture and is associated with increased TGFβ signaling. TGFβ is secreted from cells as a latent complex consisting of TGFβ, the TGFβ propeptide, and a molecule of latent TGFβ binding protein (LTBP). Improper extracellular localization of the latent complex can alter active TGFβ levels, and has been hypothesized as an explanation for enhanced TGFβ signaling observed in MFS. We previously reported the absence of LTBP-3 in matrices lacking fibrillin-1, suggesting that perturbed TGFβ signaling in MFS might be due to defective interaction of latent TGFβ complexes containing LTBP-3 with mutant fibrillin-1 microfibrils. To test this hypothesis, we genetically suppressed Ltbp3 expression in a mouse model of progressively severe MFS. Here, we present evidence that MFS mice lacking LTBP-3 have improved survival, essentially no aneurysms, reduced disruption and fragmentation of medial elastic fibers, and decreased Smad2/3 and Erk1/2 activation in their aortas. These data suggest that, in MFS, improper localization of latent TGFβ complexes composed of LTBP-3 and TGFβ contributes to aortic disease progression.

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The fibrillin-1 hypomorphic mgR/mgR murine model of Marfan syndrome shows severe elastolysis in all segments of the aorta

Abstract: Our findings suggest that mgR/mgR mice could be a useful model to study aortic abnormalities in segments other than the ascending aorta in order to understand the molecular mechanisms of aortic disease in Marfan syndrome.

Cited by 40 publications

References 25 publications

Differential ascending and descending aortic mechanics parallel aneurysmal propensity in a mouse model of Marfan syndrome

Differential ascending and descending aortic mechanics parallel aneurysmal propensity in a mouse model of Marfan syndrome

Differences in genetic signaling, and not mechanical properties of the wall, are linked to ascending aortic aneurysms in fibulin-4 knockout mice

Genetic analysis of the contribution of LTBP-3 to thoracic aneurysm in Marfan syndrome

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