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).


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.

* 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

 
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