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Effect of Doxycycline on Survival in Abdominal Aortic Aneurysms in a Mouse Model
Lisa C Adams1, Julia Brangsch1,2, Jan O Kaufmann1,3,4
1Department of Radiology, Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universitaet Berlin and Humboldt-Universitaet zu Berlin, Charitéplatz 1, Berlin 10117, Germany.
Background:
Currently, there is no reliable nonsurgical treatment for abdominal aortic aneurysm (AAA). This study, therefore, investigates if doxycycline reduces AAA growth and the number of rupture-related deaths in a murine ApoE-/- model of AAA and whether gadofosveset trisodium-based MRI differs between animals with and without doxycycline treatment.
Methods:
Nine ApoE-/- mice were implanted with osmotic minipumps continuously releasing angiotensin II and treated with doxycycline (30 mg/kg/d) in parallel. After four weeks, MRI was performed at 3T with a clinical dose of the albumin-binding probe gadofosveset (0.03 mmol/kg). Results were compared with previously published wild-type control animals and with previously studied ApoE-/- animals without doxycycline treatment. Differences in mortality were also investigated between these groups.
Results:
In a previous study, we found that approximately 25% of angiotensin II-infused ApoE-/- mice died, whereas in the present study, only one out of 9 angiotensin II-infused and doxycycline-treated ApoE-/- mice (11.1%) died within 4 weeks. Furthermore, doxycycline-treated ApoE-/- mice showed significantly lower contrast-to-noise (CNR) values (p=0.017) in MRI compared to ApoE-/- mice without doxycycline treatment. In vivo measurements of relative signal enhancement (CNR) correlated significantly with ex vivo measurements of albumin staining (R 2 = 0.58). In addition, a strong visual colocalization of albumin-positive areas in the fluorescence albumin staining with gadolinium distribution in LA-ICP-MS was shown. However, no significant difference in aneurysm size was observed after doxycycline treatment.
Conclusion:
The present experimental in vivo study suggests that doxycycline treatment may reduce rupture-related deaths in AAA by slowing endothelial damage without reversing aneurysm growth.
Insights
Doxycycline treatment may reduce rupture-related deaths in abdominal aortic aneurysms (AAA) by slowing endothelial damage. This study in mice showed lower mortality and reduced MRI contrast-to-noise ratios with doxycycline, though aneurysm size did not change.
Area of Science:
- Biomedical research
- Cardiovascular science
- Pharmacology
Background:
- Abdominal aortic aneurysm (AAA) lacks effective nonsurgical treatments.
- Investigating doxycycline's potential in managing AAA progression and rupture-related mortality.
- Assessing MRI contrast agent differences with doxycycline treatment in a murine AAA model.
Purpose of the Study:
- To evaluate doxycycline's effect on AAA growth and rupture-related deaths.
- To determine if gadofosveset trisodium-based MRI differs between doxycycline-treated and untreated AAA models.
- To explore doxycycline's mechanism in mitigating AAA-related complications.
Main Methods:
- Utilized ApoE-/- mice with angiotensin II infusion to induce AAA.
- Administered doxycycline (30 mg/kg/d) and performed 3T MRI with gadofosveset.
- Compared mortality and MRI findings with historical control groups (wild-type and untreated ApoE-/-).
Main Results:
- Doxycycline treatment reduced mortality from 25% to 11.1% in treated ApoE-/- mice.
- Significantly lower contrast-to-noise ratios (CNR) observed in doxycycline-treated mice via MRI (p=0.017).
- In vivo CNR correlated with ex vivo albumin staining, indicating reduced endothelial damage; aneurysm size remained unchanged.
Conclusions:
- Doxycycline may reduce rupture-related deaths in AAA by mitigating endothelial damage.
- The study suggests a potential therapeutic role for doxycycline in AAA management.
- MRI with albumin-binding contrast agents can detect treatment-related changes in vascular integrity.
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