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Erythropoietin promotes abdominal aortic aneurysm via angiogenesis and inflammatory infiltration in Apoe-/- and wild type mice

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE174556 | GEO | 2021/05/18

REPOSITORIES: GEO

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Project description:Tumor necrosis factor (TNF) is elevated in human abdominal aortic aneurysms (AAA). Non-selective TNF inhibition has been linked to several severe side effects. Compounds that target the proinflammatory soluble TNF (solTNF) while preserving the immunomodulatory capabilities of transmembrane TNF (tmTNF) may prevent such side effects. We hypothesize that inhibition of solTNF signaling by XPro1595 is just as effective as non-selective TNF inhibition by etanercept (ETN) in preventing AAA expansion. The effect of XPro1595 and ETN was examined in porcine pancreatic elastase (PPE) induced AAA mice and findings of XPro1595 was confirmed in Angiotensin II (AngII) induced AAA in hyperlipidemic apolipoprotein E (Apoe) -/- mice. XPro1595 treatment significantly reduced AAA expansion in both models, while a similar trend (p=0.06) was observed in ETN-treated mice using the PPE model. In the PPE aneurysm wall, elastin integrity scores were significantly improved in the XPro1595 group. In the aneurysms, mean TNFR1wasreduced no-significantly (p=0.07) by 50% non-significant after TNF inhibition, but the cellular location in murine AAAs were unaffected and like the localization in human AAAs. Systemic TNF levels were elevated in XPro1595-treated mice, while systemic IL-10 levels were significantly increased after ETN-treatment, while in AngII induced AAA mice systemic TNF and IL5 levels were elevated after XPro1595 treatment. In early AAA development, proteomic analyses revealed that components of the fibrinogen complex were elevated while prostaglandin E2 synthase was down regulated by Xpro1595 (unadjusted p-values). David’s ontology analyses revealed that several pathways including cell matrix adhesion, extracellular space, fibrinogen complex, blood microparticles and glycoproteins were elevated by XPro1595 treatment. In conclusion, selective inhibition of solTNF reduces aneurysm expansion. This supports targeting solTNF as an attractive treatment option for AAA patients.

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Erythropoietin promotes abdominal aortic aneurysm via angiogenesis and inflammatory infiltration in Apoe-/- and wild type mice

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