An animal model of EPO-induced abdominal aortic aneurysm in WT and Apoe-/- mice.
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ABSTRACT:
SUBMITTER: Zhang M
PROVIDER: S-EPMC9792537 | biostudies-literature | 2022 Dec
REPOSITORIES: biostudies-literature
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An animal model of EPO-induced abdominal aortic aneurysm in WT and Apoe<sup>-/-</sup> mice.
Zhang Meng M Sui Wenhai W Zhang Meng M Zhang Yun Y Zhang Cheng C
STAR protocols 20221215 1
Abdominal aortic aneurysm (AAA) is a potentially fatal vascular disease, but the underlying mechanisms remain obscure. Here, we provide a protocol using erythropoietin (EPO) to induce the formation of AAA in both wild-type (WT) and apolipoprotein E (Apoe<sup>-/-</sup>) mice. We describe the dose, manner, and timing of EPO administration. We also detail mice dissection, aorta isolation, and histological analysis. The animal model of EPO-induced AAA provides a useful tool for exploring the mechani ...[more]
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Project description:The present study was undertaken to test the hypothesis that EPO may promote the formation of abdominal aortic aneurysm (AAA) via angiogenesis and inflammatory response. We injected EPO in different doses to Apoe-/- and WT mice, used EPO mAb in Apoe-/- mice with AngII stimulation, injected a selective activator of the heterodimer receptors of EPO into Apoe-/- and WT mice, and created CRISPR-mediated EPOR knockout (Epor+/-Apoe-/-) mice. In addition, we measured serum EPO concentration in healthy controls and patients with AAA, and performed a series of in vitro and ex vivo experiments in ECs, SMCs, and macrophages. Our results showed that EPO dose-dependently promoted the formation of AAA, with a high occurrence rate in both Apoe-/- and WT mice, and there was a close relationship between serum concentration of EPO and the incidence of AAA in Apoe-/- and WT mice receiving AngII or EPO treatment. The major mechanism involved angiogenesis, inflammatory response, SMCs apoptosis and collagen degradation via EPO-EPOR-JAK2/STAT5 signaling pathway in vascular cells. Administration of EPO neutralizing antibody suppressed AngII-induced AAA formation, and the incidence of AAA was dramatically reduced in Epor+/-Apoe-/- versus Apoe-/- mice after AngII infusion. In addition, serum EPO concentration was substantially higher in patients with AAA than in healthy subjects and correlated with the size of AAA in patients. In conclusion, EPO promotes the formation of AAA in both Apoe-/- and WT mice likely via enhanced angiogenesis, inflammation, SMCs apoptosis and collagen degradation, and EPO/EPOR signaling is essential for AngII-induced and possibly human AAA.
2021-05-18 | GSE174556 | GEO
Project description:IntroductionWe demonstrated Toll-like receptor (TLR) 4 in the pathogenesis of angiotensin II (AngII)-mediated abdominal aortic aneurysm (AAA) formation. Here, we study TLR2 in the AAA formation.MethodsMale ApoE-/- and ApoE-/-TLR2-/- mice were treated with AngII. Mice were injected with the TLR2 agonist Pam3CSK4. The incidence and severity of AAA were determined. MCP-1, MCP-5, RANTES, CXCL10, CCR5, and CXCR3 were analyzed. M1 and M2 macrophages in the aorta were detected by flow cytometry.ResultsThese studies demonstrated an increase in AAA formation in TLR2-/- mice and a decrease by Pam3CSK4. Pam3CSK4 decreased the ratio of M1/M2 and the levels of RANTES, CXCL10, CCR5, and CXCR3. Furthermore, Pam3CSK4 treatment 1 week following AngII retarded the progression of AAA.ConclusionThese data demonstrated a protective effect of TLR2 signaling on AAA in association with a decrease in the ratio of M1 to M2 macrophages and the expression of chemokines and their receptors. Furthermore, the treatment of Pam3CSK4 after AngII demonstrated a marked retardation of lesion progression. Given the fact that most AAA patients are detected late in the disease process, these findings suggest that TLR2 stimulation may play a therapeutic role in retarding disease progression.
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