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CC BY-NC-ND 4.0 · Thromb Haemost
DOI: 10.1055/s-0044-1787957
New Technologies, Diagnostic Tools and Drugs

Novel Insights into the Aortic Mechanical Properties of Mice Modeling Hereditary Aortic Diseases

Nicolo Dubacher
1   Center for Cardiovascular Genetics and Gene Diagnostics, Swiss Foundation for People with Rare Diseases, Schlieren-Zurich, Switzerland
2   Translational Cardiovascular Technologies, Department of Health Sciences, ETH Zurich, Zurich, Switzerland
,
Kaori Sugiyama
3   Institute for Advanced Research of Biosystem Dynamics, Research Institute for Science and Engineering, Waseda University, Tokyo, Japan
4   Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan
,
Jeffrey D. Smith
5   Saha Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky, United States
,
Vanessa Nussbaumer
1   Center for Cardiovascular Genetics and Gene Diagnostics, Swiss Foundation for People with Rare Diseases, Schlieren-Zurich, Switzerland
,
Máté Csonka
1   Center for Cardiovascular Genetics and Gene Diagnostics, Swiss Foundation for People with Rare Diseases, Schlieren-Zurich, Switzerland
6   Heart and Vascular Center, Semmelweis University, Budapest, Hungary
,
Szilamér Ferenczi
7   Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary
,
Krisztina J. Kovács
7   Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary
,
Sylvan M. Caspar
1   Center for Cardiovascular Genetics and Gene Diagnostics, Swiss Foundation for People with Rare Diseases, Schlieren-Zurich, Switzerland
,
Lisa Lamberti
1   Center for Cardiovascular Genetics and Gene Diagnostics, Swiss Foundation for People with Rare Diseases, Schlieren-Zurich, Switzerland
,
Janine Meienberg
1   Center for Cardiovascular Genetics and Gene Diagnostics, Swiss Foundation for People with Rare Diseases, Schlieren-Zurich, Switzerland
,
Hiromi Yanagisawa   *
4   Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan
,
Mary B. Sheppard   *
8   Department of Family and Community Medicine, University of Kentucky, Lexington, Kentucky, United States
9   Saha Aortic Center, University of Kentucky, Lexington, Kentucky, United States
,
Gabor Matyas   *
1   Center for Cardiovascular Genetics and Gene Diagnostics, Swiss Foundation for People with Rare Diseases, Schlieren-Zurich, Switzerland
10   Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
› Author Affiliations Funding This work was supported by the Isaac Dreyfus-Bernheim Stiftung and the Fondation pour la Recherche et le Traitement Médical (FRTM) as well as by National Institutes of Health NHLBI (grant number K01 HL149984) and JSPS KAKENHI (grant number JP20H03762).
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Abstract

Objective Hereditary aortic diseases (hADs) increase the risk of aortic dissections and ruptures. Recently, we have established an objective approach to measure the rupture force of the murine aorta, thereby explaining the outcomes of clinical studies and assessing the added value of approved drugs in vascular Ehlers–Danlos syndrome (vEDS). Here, we applied our approach to six additional mouse hAD models.

Material and Methods We used two mouse models (Fbn1C1041G and Fbn1mgR ) of Marfan syndrome (MFS) as well as one smooth-muscle-cell-specific knockout (SMKO) of Efemp2 and three CRISPR/Cas9-engineered knock-in models (Ltbp1, Mfap4, and Timp1). One of the two MFS models was subjected to 4-week-long losartan treatment. Per mouse, three rings of the thoracic aorta were prepared, mounted on a tissue puller, and uniaxially stretched until rupture.

Results The aortic rupture force of the SMKO and both MFS models was significantly lower compared with wild-type mice but in both MFS models higher than in mice modeling vEDS. In contrast, the Ltbp1, Mfap4, and Timp1 knock-in models presented no impaired aortic integrity. As expected, losartan treatment reduced aneurysm formation but surprisingly had no impact on the aortic rupture force of our MFS mice.

Conclusion Our read-out system can characterize the aortic biomechanical integrity of mice modeling not only vEDS but also related hADs, allowing the aortic-rupture-force-focused comparison of mouse models. Furthermore, aneurysm progression alone may not be a sufficient read-out for aortic rupture, as antihypertensive drugs reducing aortic dilatation might not strengthen the weakened aortic wall. Our results may enable identification of improved medical therapies of hADs.

Keywords

aortic aneurysms - dissections - rupture - biomechanical integrity - Efemp2 - Fbn1 - Marfan syndrome

* These authors are joint senior authors.


Supplementary Material



Publication History

Received: 03 January 2024

Accepted: 23 May 2024

Article published online:
01 July 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Lindsay ME, Dietz HC. Lessons on the pathogenesis of aneurysm from heritable conditions. Nature 2011; 473 (7347) 308-316
    CrossrefPubMedGoogle Scholar
  • 2 Verstraeten A, Luyckx I, Loeys B. Aetiology and management of hereditary aortopathy. Nat Rev Cardiol 2017; 14 (04) 197-208
    CrossrefPubMedGoogle Scholar
  • 3 Creamer TJ, Bramel EE, MacFarlane EG. Insights on the pathogenesis of aneurysm through the study of hereditary aortopathies. Genes (Basel) 2021; 12 (02) 183
    CrossrefPubMedGoogle Scholar
  • 4 Caspar SM, Dubacher N, Kopps AM, Meienberg J, Henggeler C, Matyas G. Clinical sequencing: from raw data to diagnosis with lifetime value. Clin Genet 2018; 93 (03) 508-519
    CrossrefPubMedGoogle Scholar
  • 5 Renard M, Francis C, Ghosh R. et al. Clinical validity of genes for heritable thoracic aortic aneurysm and dissection. J Am Coll Cardiol 2018; 72 (06) 605-615
    CrossrefPubMedGoogle Scholar
  • 6 Caspar SM, Dubacher N, Matyas G. More genes for thoracic aortic aneurysms and dissections. J Am Coll Cardiol 2019; 73 (04) 528-529
    CrossrefPubMedGoogle Scholar
  • 7 Humphrey JD, Milewicz DM, Tellides G, Schwartz MA. Cell biology. Dysfunctional mechanosensing in aneurysms. Science 2014; 344 (6183) 477-479
    CrossrefPubMedGoogle Scholar
  • 8 Humphrey JD, Schwartz MA, Tellides G, Milewicz DM. Role of mechanotransduction in vascular biology: focus on thoracic aortic aneurysms and dissections. Circ Res 2015; 116 (08) 1448-1461
    CrossrefPubMedGoogle Scholar
  • 9 Pierce DM, Maier F, Weisbecker H. et al. Human thoracic and abdominal aortic aneurysmal tissues: damage experiments, statistical analysis and constitutive modeling. J Mech Behav Biomed Mater 2015; 41: 92-107
    CrossrefPubMedGoogle Scholar
  • 10 Chiu P, Lee H-P, Dalal AR. et al. Relative strain is a novel predictor of aneurysmal degeneration of the thoracic aorta: an ex vivo mechanical study. JVS Vasc Sci 2021; 2: 235-246
    CrossrefPubMedGoogle Scholar
  • 11 Chittajallu SNSH, Richhariya A, Tse KM, Chinthapenta V. A review on damage and rupture modelling for soft tissues. Bioengineering (Basel) 2022; 9 (01) 26
    CrossrefPubMedGoogle Scholar
  • 12 Dubacher N, Münger J, Gorosabel MC. et al. Celiprolol but not losartan improves the biomechanical integrity of the aorta in a mouse model of vascular Ehlers-Danlos syndrome. Cardiovasc Res 2020; 116 (02) 457-465
    PubMedGoogle Scholar
  • 13 Ong K-T, Perdu J, De Backer J. et al. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet 2010; 376 (9751) 1476-1484
    CrossrefPubMedGoogle Scholar
  • 14 Frank M, Adham S, Seigle S. et al. Vascular Ehlers-Danlos syndrome: Long-term observational study. J Am Coll Cardiol 2019; 73 (15) 1948-1957
    CrossrefPubMedGoogle Scholar
  • 15 Baderkhan H, Wanhainen A, Stenborg A, Stattin E-L, Björck M. Celiprolol treatment in patients with vascular Ehlers-Danlos syndrome. Eur J Vasc Endovasc Surg 2021; 61 (02) 326-331
    CrossrefPubMedGoogle Scholar
  • 16 Gorosabel MC, Dubacher N, Meienberg J, Matyas G. Vascular Ehlers-Danlos syndrome: can the beneficial effect of celiprolol be extrapolated to bisoprolol?. Eur Heart J Cardiovasc Pharmacother 2020; 6 (03) 199-200
    CrossrefPubMedGoogle Scholar
  • 17 Judge DP, Biery NJ, Keene DR. et al. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J Clin Invest 2004; 114 (02) 172-181
    CrossrefPubMedGoogle Scholar
  • 18 Pereira L, Lee SY, Gayraud B. et al. Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci U S A 1999; 96 (07) 3819-3823
    CrossrefPubMedGoogle Scholar
  • 19 Bunton TE, Biery NJ, Myers L, Gayraud B, Ramirez F, Dietz HC. Phenotypic alteration of vascular smooth muscle cells precedes elastolysis in a mouse model of Marfan syndrome. Circ Res 2001; 88 (01) 37-43
    CrossrefPubMedGoogle Scholar
  • 20 Saeyeldin A, Zafar MA, Velasquez CA. et al. Natural history of aortic root aneurysms in Marfan syndrome. Ann Cardiothorac Surg 2017; 6 (06) 625-632
    CrossrefPubMedGoogle Scholar
  • 21 Habashi JP, Judge DP, Holm TM. et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006; 312 (5770) 117-121
    CrossrefPubMedGoogle Scholar
  • 22 Habashi JP, Doyle JJ, Holm TM. et al. Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science 2011; 332 (6027) 361-365
    CrossrefPubMedGoogle Scholar
  • 23 Bhatt AB, Buck JS, Zuflacht JP. et al. Distinct effects of losartan and atenolol on vascular stiffness in Marfan syndrome. Vasc Med 2015; 20 (04) 317-325
    CrossrefPubMedGoogle Scholar
  • 24 Cook JR, Clayton NP, Carta L. et al. Dimorphic effects of transforming growth factor-β signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for Marfan syndrome. Arterioscler Thromb Vasc Biol 2015; 35 (04) 911-917
    CrossrefPubMedGoogle Scholar
  • 25 Robertson DM, Truong DT, Cox DA. et al. Pediatric Heart Network trial of losartan vs. atenolol in children and young adults with Marfan syndrome: impact on prescription practices. Pediatr Cardiol 2023; 44 (03) 618-623
    CrossrefPubMedGoogle Scholar
  • 26 Huang J, Davis EC, Chapman SL. et al. Fibulin-4 deficiency results in ascending aortic aneurysms: a potential link between abnormal smooth muscle cell phenotype and aneurysm progression. Circ Res 2010; 106 (03) 583-592
    CrossrefPubMedGoogle Scholar
  • 27 Hucthagowder V, Sausgruber N, Kim KH, Angle B, Marmorstein LY, Urban Z. Fibulin-4: a novel gene for an autosomal recessive cutis laxa syndrome. Am J Hum Genet 2006; 78 (06) 1075-1080
    CrossrefPubMedGoogle Scholar
  • 28 Renard M, Holm T, Veith R. et al. Altered TGFbeta signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency. Eur J Hum Genet 2010; 18 (08) 895-901
    CrossrefPubMedGoogle Scholar
  • 29 Muthu ML, Tiedemann K, Fradette J, Komarova S, Reinhardt DP. Fibrillin-1 regulates white adipose tissue development, homeostasis, and function. Matrix Biol 2022; 110: 106-128
    CrossrefPubMedGoogle Scholar
  • 30 Lee VS, Halabi CM, Hoffman EP. et al; Brigham Genomic Medicine. Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans. Proc Natl Acad Sci U S A 2016; 113 (31) 8759-8764
    CrossrefPubMedGoogle Scholar
  • 31 Halabi CM, Broekelmann TJ, Lin M, Lee VS, Chu M-L, Mecham RP. Fibulin-4 is essential for maintaining arterial wall integrity in conduit but not muscular arteries. Sci Adv 2017; 3 (05) e1602532
    CrossrefPubMedGoogle Scholar
  • 32 Parker SJ, Stotland A, MacFarlane E. et al. Proteomics reveals Rictor as a noncanonical TGF-β signaling target during aneurysm progression in Marfan mice. Am J Physiol Heart Circ Physiol 2018; 315 (05) H1112-H1126
    CrossrefPubMedGoogle Scholar
  • 33 Bhushan R, Altinbas L, Jäger M. et al. An integrative systems approach identifies novel candidates in Marfan syndrome-related pathophysiology. J Cell Mol Med 2019; 23 (04) 2526-2535
    CrossrefPubMedGoogle Scholar
  • 34 Bowen CJ, Calderón Giadrosic JF, Burger Z. et al. Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome. J Clin Invest 2020; 130 (02) 686-698
    CrossrefPubMedGoogle Scholar
  • 35 Xiong W, Meisinger T, Knispel R, Worth JM, Baxter BT. MMP-2 regulates Erk1/2 phosphorylation and aortic dilatation in Marfan syndrome. Circ Res 2012; 110 (12) e92-e101
    CrossrefPubMedGoogle Scholar
  • 36 Daugherty A, Sawada H, Sheppard MB, Lu HS. Angiotensinogen as a therapeutic target for cardiovascular and metabolic diseases. Arterioscler Thromb Vasc Biol 2024; 44 (05) 1021-1030
    CrossrefPubMedGoogle Scholar
  • 37 Chen JZ, Sawada H, Ye D. et al. Deletion of AT1a (Angiotensin II Type 1a) receptor or inhibition of angiotensinogen synthesis attenuates thoracic aortopathies in Fibrillin1C1041G/+ mice. Arterioscler Thromb Vasc Biol 2021; 41 (10) 2538-2550
    CrossrefPubMedGoogle Scholar
  • 38 Chen JZ, Sawada H, Moorleghen JJ, Weiland M, Daugherty A, Sheppard MB. Aortic strain correlates with elastin fragmentation in fibrillin-1 hypomorphic mice. Circ Rep 2019; 1 (05) 199-205
    CrossrefPubMedGoogle Scholar
  • 39 Détaint D, Faivre L, Collod-Beroud G. et al. Cardiovascular manifestations in men and women carrying a FBN1 mutation. Eur Heart J 2010; 31 (18) 2223-2229
    CrossrefPubMedGoogle Scholar
  • 40 Holmes KW, Maslen CL, Kindem M. et al; GenTAC Registry Consortium. GenTAC registry report: gender differences among individuals with genetically triggered thoracic aortic aneurysm and dissection. Am J Med Genet A 2013; 161A (04) 779-786
    CrossrefPubMedGoogle Scholar
  • 41 Renard M, Muiño-Mosquera L, Manalo EC. et al. Sex, pregnancy and aortic disease in Marfan syndrome. PLoS One 2017; 12 (07) e0181166
    CrossrefPubMedGoogle Scholar
  • 42 Cassis LA, Gupte M, Thayer S. et al. ANG II infusion promotes abdominal aortic aneurysms independent of increased blood pressure in hypercholesterolemic mice. Am J Physiol Heart Circ Physiol 2009; 296 (05) H1660-H1665
    CrossrefPubMedGoogle Scholar
  • 43 Sun Y, Asano K, Sedes L. et al. Dissecting aortic aneurysm in Marfan syndrome is associated with losartan-sensitive transcriptomic modulation of aortic cells. JCI Insight 2023; 8 (10) e168793
    CrossrefPubMedGoogle Scholar
  • 44 Seeburun S, Wu S, Hemani D. et al. Insights into elastic fiber fragmentation: Mechanisms and treatment of aortic aneurysm in Marfan syndrome. Vascul Pharmacol 2023; 153: 107215
    CrossrefPubMedGoogle Scholar
  • 45 Horiguchi M, Inoue T, Ohbayashi T. et al. Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase. Proc Natl Acad Sci U S A 2009; 106 (45) 19029-19034
    CrossrefPubMedGoogle Scholar
  • 46 Papke CL, Yanagisawa H. Fibulin-4 and fibulin-5 in elastogenesis and beyond: insights from mouse and human studies. Matrix Biol 2014; 37: 142-149
    CrossrefPubMedGoogle Scholar
  • 47 Papke CL, Tsunezumi J, Ringuette L-J. et al. Loss of fibulin-4 disrupts collagen synthesis and maturation: implications for pathology resulting from EFEMP2 mutations. Hum Mol Genet 2015; 24 (20) 5867-5879
    CrossrefPubMedGoogle Scholar
  • 48 Ruddy JM, Jones JA, Spinale FG, Ikonomidis JS. Regional heterogeneity within the aorta: relevance to aneurysm disease. J Thorac Cardiovasc Surg 2008; 136 (05) 1123-1130
    CrossrefPubMedGoogle Scholar
  • 49 Jana S, Hu M, Shen M, Kassiri Z. Extracellular matrix, regional heterogeneity of the aorta, and aortic aneurysm. Exp Mol Med 2019; 51 (12) 1-15
    CrossrefPubMedGoogle Scholar
  • 50 Morisaki T, Morisaki H. Genetics of hereditary large vessel diseases. J Hum Genet 2016; 61 (01) 21-26
    CrossrefPubMedGoogle Scholar
  • 51 Neptune ER, Frischmeyer PA, Arking DE. et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 2003; 33 (03) 407-411
    CrossrefPubMedGoogle Scholar
  • 52 Pilecki B, Holm AT, Schlosser A. et al. Characterization of microfibrillar-associated protein 4 (MFAP4) as a tropoelastin- and fibrillin-binding protein involved in elastic fiber formation. J Biol Chem 2016; 291 (03) 1103-1114
    CrossrefPubMedGoogle Scholar
  • 53 Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta 2010; 1803 (01) 55-71
    CrossrefPubMedGoogle Scholar
  • 54 Roten L, Nemoto S, Simsic J. et al. Effects of gene deletion of the tissue inhibitor of the matrix metalloproteinase-type 1 (TIMP-1) on left ventricular geometry and function in mice. J Mol Cell Cardiol 2000; 32 (01) 109-120
    CrossrefPubMedGoogle Scholar
  • 55 Eskandari MK, Vijungco JD, Flores A, Borensztajn J, Shively V, Pearce WH. Enhanced abdominal aortic aneurysm in TIMP-1-deficient mice. J Surg Res 2005; 123 (02) 289-293
    CrossrefPubMedGoogle Scholar
  • 56 Todorovic V, Frendewey D, Gutstein DE. et al. Long form of latent TGF-beta binding protein 1 (Ltbp1L) is essential for cardiac outflow tract septation and remodeling. Development 2007; 134 (20) 3723-3732
    CrossrefPubMedGoogle Scholar
  • 57 Todorovic V, Finnegan E, Freyer L, Zilberberg L, Ota M, Rifkin DB. Long form of latent TGF-β binding protein 1 (Ltbp1L) regulates cardiac valve development. Dev Dyn 2011; 240 (01) 176-187
    CrossrefPubMedGoogle Scholar
  • 58 Schlosser A, Pilecki B, Hemstra LE. et al. MFAP4 promotes vascular smooth muscle migration, proliferation and accelerates neointima formation. Arterioscler Thromb Vasc Biol 2016; 36 (01) 122-133
    CrossrefPubMedGoogle Scholar
  • 59 Arpino V, Brock M, Gill SE. The role of TIMPs in regulation of extracellular matrix proteolysis. Matrix Biol 2015; 44-46: 247-254
    CrossrefPubMedGoogle Scholar
  • 60 Ritskes-Hoitinga M, Leenaars C, Beumer W, Coenen-de Roo T, Stafleu F, Meijboom FLB. Improving translation by identifying evidence for more human-relevant preclinical strategies. Animals (Basel) 2020; 10 (07) 1170
    CrossrefPubMedGoogle Scholar