An abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease. We identified plasma insulin-like growth factor 1 (IGF1) as an independent risk factor in patients with AAA by correlating plasma IGF1 with risk. Smooth muscle cell– or fibroblast-specific knockout of Igf1r , the gene encoding the IGF1 receptor (IGF1R), attenuated AAA formation in two mouse models of AAA induced by angiotensin II infusion or CaCl 2 treatment. IGF1R was activated in aortic aneurysm samples from human patients and mice with AAA. Systemic administration of IGF1C, a peptide fragment of IGF1, 2 weeks after disease development inhibited AAA progression in mice. Decreased AAA formation was linked to competitive inhibition of IGF1 binding to its receptor by IGF1C and modulation of downstream alpha serine/threonine protein kinase (AKT)/mammalian target of rapamycin signaling. Localized application of an IGF1C-loaded hydrogel was developed to reduce the side effects observed after systemic administration of IGF1C or IGF1R antagonists in the CaCl 2 -induced AAA mouse model. The inhibitory effect of the IGF1C-loaded hydrogel administered at disease onset on AAA formation was further evaluated in a guinea pig-to-rat xenograft model and in a sheep-to-minipig xenograft model of AAA formation. The therapeutic efficacy of IGF1C for treating AAA was tested through extravascular delivery in the sheep-to-minipig model with AAA established for 2 weeks. Percutaneous injection of the IGF1C-loaded hydrogel around the AAA resulted in improved vessel flow dynamics in the minipig aorta. These findings suggest that extravascular administration of IGF1R antagonists may have translational potential for treating AAA.

中文翻译：

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IGF1R 拮抗剂的血管外给药可预防啮齿动物和猪模型中的主动脉瘤


腹主动脉瘤（AAA）是一种危及生命的心血管疾病。我们通过将血浆 IGF1 与风险相关联，将血浆胰岛素样生长因子 1 (IGF1) 确定为 AAA 患者的独立危险因素。平滑肌细胞或成纤维细胞特异性敲除免疫球蛋白1r编码 IGF1 受体 (IGF1R) 的基因，在两种由血管紧张素 II 输注或 CaCl 诱导的 AAA 小鼠模型中减弱了 AAA 形成2治疗。 IGF1R 在人类患者和 AAA 小鼠的主动脉瘤样本中被激活。疾病发生 2 周后，全身给予 IGF1C（IGF1 的肽片段）可抑制小鼠 AAA 的进展。 AAA 形成的减少与 IGF1C 竞争性抑制 IGF1 与其受体的结合以及调节下游 α 丝氨酸/苏氨酸蛋白激酶 (AKT)/雷帕霉素信号传导的哺乳动物靶标有关。开发了负载 IGF1C 的水凝胶的局部应用，以减少在 CaCl 中全身施用 IGF1C 或 IGF1R 拮抗剂后观察到的副作用2诱导AAA小鼠模型。在豚鼠至大鼠异种移植模型和绵羊至小型猪异种移植 AAA 形成模型中，进一步评估了疾病发作时施用的负载 IGF1C 的水凝胶对 AAA 形成的抑制作用。通过血管外递送在建立 2 周 AAA 的绵羊至小型猪模型中测试 IGF1C 对 AAA 的治疗效果。在 AAA 周围经皮注射负载 IGF1C 的水凝胶可改善小型猪主动脉的血管流动动力学。这些发现表明 IGF1R 拮抗剂的血管外给药可能具有治疗 AAA 的转化潜力。