2. Academic Validation
  3. Extravascular administration of IGF1R antagonists protects against aortic aneurysm in rodent and porcine models

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

  • Sci Transl Med. 2024 May;16(745):eadh1763. doi: 10.1126/scitranslmed.adh1763.
Yongzhen Wei 1 2,  Huan Jiang 1,  Fengjuan Li 3,  Chao Chai 4,  Yaping Xu 5,  Mengmeng Xing 1,  Weiliang Deng 1,  He Wang 1,  Yuexin Zhu 3,  Sen Yang 6,  Yongquan Yu 7,  Wenming Wang 8,  Yan Wei 5,  Yu Guo 8,  Jinwei Tian 9,  Jie Du 3,  Zhikun Guo 5,  Yuan Wang 3,  Qiang Zhao 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China.
  • 2 The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Health Science Center, Peking University, Beijing 100191, China.
  • 3 Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Key Laboratory of Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
  • 4 Department of Radiology, Tianjin Institute of Imaging Medicine, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300192, China.
  • 5 Zhengzhou Cardiovascular Hospital and 7th People's Hospital of Zhengzhou, Zhengzhou, China.
  • 6 Department of Vascular Surgery, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China.
  • 7 Department of Radiology, Weihai Central Hospital, Weihai 264400, China.
  • 8 State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
  • 9 Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
PMID: 38691618 DOI: 10.1126/scitranslmed.adh1763
Abstract

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.

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