Celiprolol but not losartan improves the biomechanical integrity of the aorta in a mouse model of vascular Ehlers–Danlos syndrome

• Published in: Cardiovascular research 2020-02, Vol.116 (2), p.457-465
• Main Authors: Dubacher, Nicolo, Münger, Justyna, Gorosabel, Maria C, Crabb, Jessica, Ksiazek, Agnieszka A, Caspar, Sylvan M, Bakker, Erik N T P, van Bavel, Ed, Ziegler, Urs, Carrel, Thierry, Steinmann, Beat, Zeisberger, Steffen, Meienberg, Janine, Matyas, Gabor
• Format: Article
• Language: English
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvz095

Abstract Aims Antihypertensive drugs are included in the medical therapy of vascular Ehlers–Danlos syndrome (vEDS). The β-blocker celiprolol has been suggested to prevent arterial damage in vEDS, but the underlying mechanism remains unclear. It is also unknown whether the widely used angiotensin II receptor type 1 antagonist losartan has a therapeutic effect in vEDS. Here, we evaluated the impact of celiprolol and losartan on the biomechanical integrity of the vEDS thoracic aorta. Methods and results We established a new approach to measure the maximum tensile force at rupture of uniaxially stretched murine thoracic aortic rings. In a vEDS model, which we (re-)characterized here at molecular level, heterozygous mice showed a significant reduction in the rupture force compared to wild-type mice, reflecting the increased mortality due to aortic rupture. For the assessment of treatment effects, heterozygous mice at 4 weeks of age underwent a 4-week treatment with celiprolol, losartan, and, as a proof-of-concept drug, the matrix metalloproteinase inhibitor doxycycline. Compared to age- and sex-matched untreated heterozygous mice, treatment with doxycycline or celiprolol resulted in a significant increase of rupture force, whereas no significant change was detected upon losartan treatment. Conclusions In a vEDS model, celiprolol or doxycycline, but not losartan, can improve the biomechanical integrity of the aortic wall, thereby potentially reducing the risk of dissection and rupture. As doxycycline is a broad-spectrum antibiotic with considerable side effects, celiprolol may be more suitable for a long-term therapy and thus rather indicated for the medication of patients with vEDS.