Erythropoietin promotes abdominal aortic aneurysms in mice through angiogenesis and inflammatory infiltration
Erythropoietin promotes abdominal aortic aneurysms in mice through angiogenesis and inflammatory infiltration
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促红细胞生成素通过血管生成和炎症浸润促进小鼠腹主动脉瘤
DOI：
10.1126/scitranslmed.aaz4959
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发表时间：
2021-07-21
影响因子：
17.1
通讯作者：
Zhang，Cheng
中科院分区：
文献类型：
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作者：
Zhang，Meng L.;Sui，Wenhai;Zhang，Cheng
促红细胞生成素通过JAK 2/STAT 5信号传导剂量依赖性地诱导小鼠腹主动脉瘤，即使没有血管紧张素II输注。促红细胞生成素与腹主动脉瘤腹主动脉瘤是一种常见的血管疾病，但其发病机制尚未完全阐明。在这里，Zhang及其同事通过给予高剂量的促红细胞生成素开发了AAA的小鼠模型，这导致了动脉瘤形成，而不管ApoE状态或血管紧张素II输注如何，这与常用的小鼠AAA模型不同。内皮细胞对于促红细胞生成素对主动脉的作用至关重要，并且JAK 2/STAT 5通路活化与该过程有关。作者还发现患者中促红细胞生成素浓度与AAA之间存在相关性，这表明促红细胞生成素与AAA之间的联系值得在人类中进一步研究。腹主动脉瘤（AAA）是一种潜在的致命性血管疾病，但其潜在机制尚不清楚。在这里，我们测试的假设，促红细胞生成素（EPO）可能会促进AAA的形成。我们发现，EPO剂量依赖性地促进了接受高剂量EPO的Apoe−/−（66.7%）和野生型（WT）（60%）小鼠AAA的形成。给予接受血管紧张素II（AngII）刺激的Apoe−/−小鼠EPO单克隆抗体导致AAA发生率显著降低（从86.7%到20%，P < 0.001），与AngII刺激后的Apoe−/−小鼠相比，Epor+/−Apoe−/−小鼠中EPO受体（EPOR）敲低显著降低了AAA的发生率（从86.7%到45.5%，P < 0.05），进一步支持EPO是AAA形成的贡献者的发现。EPO诱导的AAA导致微血管、吞噬细胞浸润和基质金属蛋白酶分泌增加，以及胶原和平滑肌细胞（SMC）减少。体外和离体实验表明，EPO通过JAK 2/STAT 5信号通路诱导内皮细胞增殖、迁移和管形成。在人类中，AAA患者的血清EPO浓度高于健康个体，并且与AAA的大小相关，这表明EPO与人类AAA的严重程度之间存在潜在联系。总之，我们发现EPO通过增强血管生成、炎症、胶原降解和SMC凋亡促进Apoe−/−和WT小鼠中AAA的形成，并且EPO/EPOR信号传导对于AngII诱导的AAA至关重要。EPO和AAA在人类中的关联值得进一步研究。
Erythropoietin dose-dependently induces abdominal aortic aneurysm in mice via JAK2/STAT5 signaling, even without angiotensin II infusion. Erythropoietin and AAA Abdominal aortic aneurysm (AAA) is a common vascular disease, but its pathogenesis has not been fully elucidated. Here, Zhang and colleagues developed a murine model of AAA by administering high doses of erythropoietin, which led to aneurysm formation regardless of ApoE status or angiotensin II infusion, unlike the commonly used murine AAA model. Endothelial cells were critical to erythropoietin’s effects on the aorta, and JAK2/STAT5 pathway activation was implicated in this process. The authors also found a correlation between erythropoietin concentrations and AAA in patients, suggesting that the link between erythropoietin and AAA deserves further investigation in humans. Abdominal aortic aneurysm (AAA) is a potentially fatal vascular disease, but the underlying mechanisms remain unknown. Here, we tested the hypothesis that erythropoietin (EPO) may promote the formation of AAA. We found that EPO dose-dependently promoted the formation of AAA in both Apoe−/− (66.7%) and wild-type (WT) (60%) mice receiving a high dose of EPO. EPO monoclonal antibodies given to Apoe−/− mice receiving angiotensin II (AngII) stimulation resulted in a markedly lower incidence of AAA (from 86.7 to 20%, P < 0.001), and EPO receptor (EPOR) knockdown in Epor+/−Apoe−/− mice substantially reduced the incidence of AAA compared to Apoe−/− mice after AngII stimulation (from 86.7 to 45.5%, P < 0.05), further supporting the finding that EPO is a contributor to AAA formation. EPO-induced AAA resulted in increased microvessels, phagocyte infiltration, and matrix metalloproteinase secretion, as well as reduced collagen and smooth muscle cells (SMCs). Experiments in vitro and ex vivo demonstrated that EPO induced proliferation, migration, and tube formation of endothelial cells via the JAK2/STAT5 signaling pathway. In humans, serum EPO concentrations were higher in patients with AAA than in healthy individuals and correlated with the size of the AAA, suggesting a potential link between EPO and the severity of AAA in humans. In conclusion, we found that EPO promotes the formation of AAA in both Apoe−/− and WT mice by enhancing angiogenesis, inflammation, collagen degradation, and apoptosis of SMCs and that EPO/EPOR signaling is essential for AngII-induced AAA. The association between EPO and AAA in humans warrants further study.