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

<p>Aortic aneurysm is a life-threatening cardiovascular disease with high mortality. Herein, we first identified that plasma IGF1 was an independent risk factor in patients with abdominal aortic aneurysm. The IGF1 receptor was also activated in aneurysmal aortas from humans and mice, and SMC- or fibroblast-specific knockout of IGF1R attenuated AAA formation in mouse models, indicating the potential of IGF1R as a therapeutic target. Systemic administration of IGF1C peptide exerted an evident inhibitory effect on AAA formation and progression via competitive inhibition of IGF1 binding to its receptor and modulation of downstream AKT/mTOR signaling. However, global inhibition of IGF1R signaling induces side effects, including abnormal glucose metabolism, muscular disorder, and pain hypersensitivity observed after systemic administration of IGF1C or the commercialized IGF1R antagonists. Accordingly, local administration of IGF1C was realized via ultrasound-guided percutaneous injection of an IGF1C-loaded hydrogel, and the therapeutic efficacy was confirmed in a pig AAA model, demonstrating its translational potential for AAA therapy.</p>