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

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 CaCl₂ 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 CaCl₂-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. Editor's summary: An abdominal aortic aneurysm (AAA) is life threatening and has limited therapeutic options. Wei et al. showed that localized inhibition of insulin-like growth factor 1 receptor (IGF1R) protected against AAA. Humans with AAA had increased IGF1 and IGF1R in aortic tissue. In mice treated with angiotensin II infusion or calcium chloride to induce AAA, IGF1R was increased, and genetic deletion of Igf1r in smooth muscle cells or fibroblasts decreased AAA pathology. IGF1C, a peptide fragment of IGF1, inhibited IGF1R in human cells in culture and in the two mouse models, resulting in decreased AAA pathology. In both a rat and minipig model of aorta xenotransplantation to induce AAA, the application of a hydrogel containing IGF1C to the aorta decreased AAA pathology. Inhibiting IGF1R in AAA may be a treatment for slowing AAA. —Brandon Berry [ABSTRACT FROM AUTHOR]