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. [1 ]
de Souza, Rodrigo Barbosa [2 ]
Herrick, Ashley [1 ]
Pereira, Lygia V. [2 ]
Bellini, Chiara [1 ]
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.
引用
收藏
页数:14
相关论文
共 85 条
[1]   Perlecan is essential for cartilage and cephalic development [J].
Arikawa-Hirasawa, E ;
Watanabe, H ;
Takami, H ;
Hassell, JR ;
Yamada, Y .
NATURE GENETICS, 1999, 23 (03) :354-358
[2]   Association of modifiers and other genetic factors explain Marfan syndrome clinical variability [J].
Aubart, Melodie ;
Gazal, Steven ;
Arnaud, Pauline ;
Benarroch, Louise ;
Gross, Marie-Sylvie ;
Buratti, Julien ;
Boland, Anne ;
Meyer, Vincent ;
Zouali, Habib ;
Hanna, Nadine ;
Milleron, Olivier ;
Stheneur, Chantal ;
Bourgeron, Thomas ;
Desguerre, Isabelle ;
Jacob, Marie-Paule ;
Gouya, Laurent ;
Genin, Emmanuelle ;
Deleuze, Jean-Francois ;
Jondeau, Guillaume ;
Boileau, Catherine .
EUROPEAN JOURNAL OF HUMAN GENETICS, 2018, 26 (12) :1759-1772
[3]   Theory of small on large: Potential utility in computations of fluid-solid interactions in arteries [J].
Baek, S. ;
Gleason, R. L. ;
Rajagopal, K. R. ;
Humphrey, J. D. .
COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING, 2007, 196 (31-32) :3070-3078
[4]   Comparison of 10 murine models reveals a distinct biomechanical phenotype in thoracic aortic aneurysms [J].
Bellini, C. ;
Bersi, M. R. ;
Caulk, A. W. ;
Ferruzzi, J. ;
Milewicz, D. M. ;
Ramirez, F. ;
Rifkin, D. B. ;
Tellides, G. ;
Yanagisawa, H. ;
Humphrey, J. D. .
JOURNAL OF THE ROYAL SOCIETY INTERFACE, 2017, 14 (130)
[5]   Differential ascending and descending aortic mechanics parallel aneurysmal propensity in a mouse model of Marfan syndrome [J].
Bellini, C. ;
Korneva, A. ;
Zilberberg, L. ;
Ramirez, F. ;
Rifldn, D. B. ;
Humphrey, J. D. .
JOURNAL OF BIOMECHANICS, 2016, 49 (12) :2383-2389
[6]   Differential cell-matrix mechanoadaptations and inflammation drive regional propensities to aortic fibrosis, aneurysm or dissection in hypertension [J].
Bersi, M. R. ;
Khosravi, R. ;
Wujciak, A. J. ;
Harrison, D. G. ;
Humphrey, J. D. .
JOURNAL OF THE ROYAL SOCIETY INTERFACE, 2017, 14 (136)
[7]   Novel interactions of perlecan: Unraveling perlecan's role in angiogenesis [J].
Bix, Gregory ;
Iozzo, Renato V. .
MICROSCOPY RESEARCH AND TECHNIQUE, 2008, 71 (05) :339-348
[8]   Aortic dissecting aneurysms-Histopathological findings [J].
Bode-Jaenisch, S. ;
Schmidt, A. ;
Guenther, D. ;
Stuhrmann, M. ;
Fieguth, A. .
FORENSIC SCIENCE INTERNATIONAL, 2012, 214 (1-3) :13-17
[9]   Progressive Microstructural Deterioration Dictates Evolving Biomechanical Dysfunction in the Marfan Aorta [J].
Cavinato, Cristina ;
Chen, Minghao ;
Weiss, Dar ;
Ruiz-Rodriguez, Maria Jesus ;
Schwartz, Martin A. ;
Humphrey, Jay D. .
FRONTIERS IN CARDIOVASCULAR MEDICINE, 2021, 8
[10]   FN (Fibronectin)-Integrin α5 Signaling Promotes Thoracic Aortic Aneurysm in a Mouse Model of Marfan Syndrome [J].
Chen, Minghao ;
Cavinato, Cristina ;
Hansen, Jens ;
Tanaka, Keiichiro ;
Ren, Pengwei ;
Hassab, Abdulrahman ;
Li, David S. ;
Youshao, Eric ;
Tellides, George ;
Iyengar, Ravi ;
Humphrey, Jay D. ;
Schwartz, Martin A. .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2023, 43 (05) :E132-E150