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Arterial Injury in Mice with Severe Insulin-Like Growth Factor-1 (IGF-1) Deficiency

Paul Dimayuga, PhD

Makoto Yamashita, MD

Juliana Yano, BS

Atherosclerosis Research Center; Division of Cardiology, Los Angeles, CA

Mario Fournier, PhD

Michael Lewis, MD

Pulmonary Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.

Bojan Cercek, MD, PhD

Atherosclerosis Research Center; Division of Cardiology, Los Angeles, CA

Background: Insulin-like growth factor-1 plays a significant role in wound healing. Injury to the arterial wall is followed by a marked increase in insulin-like growth factor-1 expression and inhibition of insulin-like growth factor-1 action is associated with diminished intimal thickening after injury.

Methods and Results: The role of insulin-like growth factor-1 in arterial response to cuffinjury was investigated in genetically modified mice with severe insulin-like growth factor-1 deficiency (^m/m mice). Tissue and serum insulin-like growth factor-1 was severely decreased, by 40% to 60% before the injury and by 50% to 60% following the arterial injury in insulin-like growth factor-1 ^m/m mice compared to control mice. Nevertheless, following the cuff induced injury to the carotid arteries, insulin-like growth factor-1^m/m mice had a similar number of proliferating medial cells 3 days after injury and similar neointimal thickening (0.019 ± 0.015 C57BL/6J vs. 0.016 ± 0.014 mm², P = 0.26) 21 days after injury compared to wild type C57BL/6J mice. The phases of the response to injury that are mediated by insulin-like growth factor-1 were studied with recombinant human insulin-like growth factor-1 in rats with balloon-injured femoral arteries. Treatment of rats with recombinant human insulin-like growth factor-1 increased neointimal thickening (0.0265 ± 0.0099 vs 0.0156 ± 0.0049 mm², P = 0.03), intimal smooth muscle cell numbers (195.6 ± 40.2 vs 145.3±27.3; P = 0.03), and the ratio of proliferating intimal to medial smooth muscle cells (10.7 ± 6.9 vs 3.0 ± 2.1; P = 0.03) 7 days after injury compared to untreated rats. At 14 days neointimal area was similar in the 2 groups of rats.

Conclusions: The data in insulin-like growth factor-1 deficient mice suggest a relatively low threshold tissue concentration for insulin-like growth factor-1 to exhibit its role in vascular response to injury. The findings in rats treated with recombinant human insulin-like growth factor-1 suggest that insulin-like growth factor-1 is primarily involved in the early phases of neointimal formation.

Key Words: neointima • smooth muscle cells • proliferation • insulin-like growth factor-1

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 7, No. 4, 227-233 (2002)
DOI: 10.1177/107424840200700405


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