共 85 条
The Fbn1 gene variant governs passive ascending aortic mechanics in the mgΔlpn mouse model of Marfan syndrome when superimposed to perlecan haploinsufficiency
被引:2
作者:

Tarraf, Samar A.
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Northeastern Univ, Dept Bioengn, Boston, MA 02120 USA Northeastern Univ, Dept Bioengn, Boston, MA 02120 USA

de Souza, Rodrigo Barbosa
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机构:
Univ Sao Paulo, Dept Genet & Evolutionary Biol, Sao Paulo, Brazil Northeastern Univ, Dept Bioengn, Boston, MA 02120 USA

Herrick, Ashley
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Northeastern Univ, Dept Bioengn, Boston, MA 02120 USA Northeastern Univ, Dept Bioengn, Boston, MA 02120 USA

Pereira, Lygia V.
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Univ Sao Paulo, Dept Genet & Evolutionary Biol, Sao Paulo, Brazil Northeastern Univ, Dept Bioengn, Boston, MA 02120 USA

论文数: 引用数:
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机构:
[1] Northeastern Univ, Dept Bioengn, Boston, MA 02120 USA
[2] Univ Sao Paulo, Dept Genet & Evolutionary Biol, Sao Paulo, Brazil
关键词:
ascending aneurysm;
biomechanics;
Marfan syndrome;
fibrillin-1;
perlecan;
ELASTIC FIBER INTEGRITY;
ANEURYSM;
PATHOGENESIS;
MICROFIBRILS;
DISSECTIONS;
FIBRONECTIN;
ASSOCIATION;
MANAGEMENT;
CARTILAGE;
DISEASES;
D O I:
10.3389/fcvm.2024.1319164
中图分类号:
R5 [内科学];
学科分类号:
1002 ;
100201 ;
摘要:
Introduction: Ascending thoracic aortic aneurysms arise from pathological tissue remodeling that leads to abnormal wall dilation and increases the risk of fatal dissection/rupture. Large variability in disease manifestations across family members who carry a causative genetic variant for thoracic aortic aneurysms suggests that genetic modifiers may exacerbate clinical outcomes. Decreased perlecan expression in the aorta of mg Delta(lpn) mice with severe Marfan syndrome phenotype advocates for exploring perlecan-encoding Hspg2 as a candidate modifier gene. Methods: To determine the effect of concurrent Hspg2 and Fbn1 mutations on the progression of thoracic aortopathy, we characterized the microstructure and passive mechanical response of the ascending thoracic aorta in female mice of four genetic backgrounds: wild-type, heterozygous with a mutation in the Fbn1 gene (mg Delta(lpn)), heterozygous with a mutation in the Hspg2 gene (Hspg2(+/-)), and double mutants carrying both the Fbn1 and Hspg2 variants (dMut). Results: Elastic fiber fragmentation and medial disarray progress from the internal elastic lamina outward as the ascending thoracic aorta dilates in mg Delta(lpn) and dMut mice. Concurrent increase in total collagen content relative to elastin reduces energy storage capacity and cyclic distensibility of aortic tissues from mice that carry the Fbn1 variant. Inherent circumferential tissue stiffening strongly correlates with the severity of aortic dilatation in mg Delta(lpn) and dMut mice. Perlecan haploinsufficiency superimposed to the mg Delta(lpn) mutation curbs the viability of dMut mice, increases the occurrence of aortic enlargement, and reduces the axial stretch in aortic tissues. Discussion: Overall, our findings show that dMut mice are more vulnerable than mg Delta(lpn) mice without an Hspg2 mutation, yet later endpoints and additional structural and functional readouts are needed to identify causative mechanisms.
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Humphrey, Jay D.
;
Schwartz, Martin A.
.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY,
2023, 43 (05)
:E132-E150

Chen, Minghao
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h-index: 0
机构:
Yale Sch Med, Cardiovasc Res Ctr, New Haven, CT USA Yale CVRC, 300 George St,7th floor, New Haven, CT 06511 USA

Cavinato, Cristina
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Yale Univ, Dept Biomed Engn, New Haven, CT USA Yale CVRC, 300 George St,7th floor, New Haven, CT 06511 USA

Hansen, Jens
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h-index: 0
机构:
Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY USA
Icahn Sch Med Mt Sinai, Inst Syst Biomed, New York, NY USA Yale CVRC, 300 George St,7th floor, New Haven, CT 06511 USA

Tanaka, Keiichiro
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h-index: 0
机构:
Yale Sch Med, Cardiovasc Res Ctr, New Haven, CT USA Yale CVRC, 300 George St,7th floor, New Haven, CT 06511 USA

Ren, Pengwei
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h-index: 0
机构:
Yale Sch Med, Dept Surg, New Haven, CT USA Yale CVRC, 300 George St,7th floor, New Haven, CT 06511 USA

Hassab, Abdulrahman
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Yale Sch Med, Dept Surg, New Haven, CT USA Yale CVRC, 300 George St,7th floor, New Haven, CT 06511 USA

Li, David S.
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机构:
Yale Univ, Dept Biomed Engn, New Haven, CT USA Yale CVRC, 300 George St,7th floor, New Haven, CT 06511 USA

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Tellides, George
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h-index: 0
机构:
Yale Sch Med, Dept Surg, New Haven, CT USA
Yale Sch Med, Vasc Biol & Therapeut Program, New Haven, CT USA Yale CVRC, 300 George St,7th floor, New Haven, CT 06511 USA

Iyengar, Ravi
论文数: 0 引用数: 0
h-index: 0
机构:
Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY USA
Icahn Sch Med Mt Sinai, Inst Syst Biomed, New York, NY USA Yale CVRC, 300 George St,7th floor, New Haven, CT 06511 USA

Humphrey, Jay D.
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h-index: 0
机构:
Yale Sch Med, Vasc Biol & Therapeut Program, New Haven, CT USA
Yale Univ, Dept Biomed Engn, New Haven, CT USA Yale CVRC, 300 George St,7th floor, New Haven, CT 06511 USA

Schwartz, Martin A.
论文数: 0 引用数: 0
h-index: 0
机构:
Yale CVRC, 300 George St,7th floor, New Haven, CT 06511 USA
Yale Sch Med, Cardiovasc Res Ctr, New Haven, CT USA
Yale Sch Med, Dept Surg, New Haven, CT USA
Yale Sch Med, Dept Med Cardiol & Cell Biol MAS, New Haven, CT USA
Yale Univ, Dept Biomed Engn, New Haven, CT USA Yale CVRC, 300 George St,7th floor, New Haven, CT 06511 USA