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Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice
Published on: September 28, 2015
Angiotensin II Infusion Leads to Aortic Dissection in LRP8 Deficient Mice
Jeremy Lagrange1,2, Stefanie Finger1, Sabine Kossmann1,3,4
1Center for Thrombosis and Hemostasis, University Medical Center Mainz, 55131 Mainz, Germany.
Abstract:
Myeloid cells are crucial for the development of vascular inflammation. Low-density lipoprotein receptor-related protein 8 (LRP8) or Apolipoprotein E receptor 2 (ApoER2), is expressed by macrophages, endothelial cells and platelets and has been implicated in the development of cardiovascular diseases. Our aim was to evaluate the role of LRP8, in particular from immune cells, in the development of vascular inflammation.
Methods:
LRP8+/+ and LRP8-/- mice (on B6;129S background) were infused with angiotensin II (AngII, 1 mg/kg/day for 7 to 28 day) using osmotic minipumps. Blood pressure was recorded using tail cuff measurements. Vascular reactivity was assessed in isolated aortic segments. Leukocyte activation and infiltration were assessed by flow cytometry of aortic tissue and intravital videomicroscopy imaging. Histological analysis of aortic sections was conducted using sirius red staining.
Results:
AngII infusion worsened endothelial-dependent vascular relaxation and immune cells rolling and adherence to the carotid artery in both LRP8+/+ as well as LRP8-/- mice. However, only LRP8-/- mice demonstrated a drastically increased mortality rate in response to AngII due to aortic dissection. Bone marrow transplantation revealed that chimeras with LRP8 deficient myeloid cells phenocopied LRP8-/- mice.
Conclusion:
AngII-infused LRP8 deficient mice could be a useful animal model to study aortic dissection reflecting the lethality of this disease in humans.
Insights
Low-density lipoprotein receptor-related protein 8 (LRP8) deficiency in myeloid cells exacerbates vascular inflammation and mortality from aortic dissection in mice. LRP8 plays a critical role in immune cell function during vascular disease.
Area of Science:
- Cardiovascular Biology
- Immunology
- Vascular Inflammation
Background:
- Myeloid cells are key drivers of vascular inflammation.
- Low-density lipoprotein receptor-related protein 8 (LRP8), also known as Apolipoprotein E receptor 2 (ApoER2), is expressed in immune cells and linked to cardiovascular diseases.
Purpose of the Study:
- To investigate the role of LRP8, specifically within immune cells, in the development of vascular inflammation and associated pathologies.
Main Methods:
- LRP8-deficient (LRP8-/-) and wild-type (LRP8+/+) mice were infused with angiotensin II (AngII).
- Vascular function, leukocyte activation/infiltration, and mortality were assessed.
- Bone marrow transplantation was used to determine the role of myeloid LRP8.
Main Results:
- AngII infusion impaired vascular relaxation and increased leukocyte adhesion in both genotypes.
- LRP8-/- mice exhibited significantly higher mortality due to aortic dissection following AngII infusion.
- Myeloid cell-specific LRP8 deficiency recapitulated the severe phenotype of LRP8-/- mice.
Conclusions:
- LRP8 deficiency in myeloid cells critically contributes to AngII-induced aortic dissection and mortality.
- Angiotensin II-infused LRP8-deficient mice represent a valuable model for studying the lethality of aortic dissection.
