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

Nicolo Dubacher; Kaori Sugiyama; Jeffrey D. Smith; Vanessa Nussbaumer; Máté Csonka; Szilamér Ferenczi; Krisztina J. Kovács; Sylvan M. Caspar; Lisa Lamberti; Janine Meienberg; Hiromi Yanagisawa; Mary B. Sheppard; Gabor Matyas

doi:10.1055/s-0044-1787957

Thrombosis and Haemostasis, Table of Contents

CC BY-NC-ND 4.0 · Thromb Haemost 2025; 125(02): 142-152
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

Authors

Nicolo Dubacher

¹Center for Cardiovascular Genetics and Gene Diagnostics, Swiss Foundation for People with Rare Diseases, Schlieren-Zurich, Switzerland

²Translational Cardiovascular Technologies, Department of Health Sciences, ETH Zurich, Zurich, Switzerland
Kaori Sugiyama

³Institute for Advanced Research of Biosystem Dynamics, Research Institute for Science and Engineering, Waseda University, Tokyo, Japan

⁴Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan
Jeffrey D. Smith

⁵Saha Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky, United States
Vanessa Nussbaumer

¹Center for Cardiovascular Genetics and Gene Diagnostics, Swiss Foundation for People with Rare Diseases, Schlieren-Zurich, Switzerland
Máté Csonka

¹Center for Cardiovascular Genetics and Gene Diagnostics, Swiss Foundation for People with Rare Diseases, Schlieren-Zurich, Switzerland

⁶Heart and Vascular Center, Semmelweis University, Budapest, Hungary
Szilamér Ferenczi

⁷Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary
Krisztina J. Kovács

⁷Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary
Sylvan M. Caspar

¹Center for Cardiovascular Genetics and Gene Diagnostics, Swiss Foundation for People with Rare Diseases, Schlieren-Zurich, Switzerland
Lisa Lamberti

¹Center for Cardiovascular Genetics and Gene Diagnostics, Swiss Foundation for People with Rare Diseases, Schlieren-Zurich, Switzerland
Janine Meienberg

¹Center for Cardiovascular Genetics and Gene Diagnostics, Swiss Foundation for People with Rare Diseases, Schlieren-Zurich, Switzerland
Hiromi Yanagisawa^*

⁴Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan
Mary B. Sheppard^*

⁸Department of Family and Community Medicine, University of Kentucky, Lexington, Kentucky, United States

⁹Saha Aortic Center, University of Kentucky, Lexington, Kentucky, United States
Gabor Matyas^*

¹Center for Cardiovascular Genetics and Gene Diagnostics, Swiss Foundation for People with Rare Diseases, Schlieren-Zurich, Switzerland

¹⁰Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland

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 (Fbn1^C1041G and Fbn1^mgR ) 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

Full Text

References

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