Extravascular administration of IGF1R antagonists protects against aortic aneurysm in rodent and porcine models

作者：Yongzhen Wei, Yongzhen Wei, Huan Jiang, Fengjuan Li, Chao Chai, Yaping Xu, Mengmeng Xing, Weiliang Deng, He Wang, Yuexin Zhu, Sen Yang, Yongquan Yu, Wenming Wang, Yan Wei, Yan Wei, Yu Guo, Jinwei Tian, Jie Du, Zhikun Guo, Yuan Wang, Qiang Zhao · 发表于：Science Translational Medicine · 年份：2024 · DOI：10.1126/scitranslmed.adh1763 · 被引用次数：17 · 研究领域：Aortic aneurysm repair treatments、Aortic Disease and Treatment Approaches、Connective tissue disorders research

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 hydro...