Targeted Overexpression of IGF-I in Smooth Muscle Cells of Transgenic Mice Enhances Neointimal Formation through Increased Proliferation and Cell Migration after Intraarterial Injury

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Abstract
The response of arterial smooth muscle cells to injury is governed by a complex series of events. Significant among them is the paracrine production of peptide growth factors. To determine the impact of local IGF-I gene expression on vascular injury, the left carotid arteries of SMP8-IGF-I mice (in which IGF-I is selectively overexpressed in smooth muscle cells by means of a smooth muscle α-actin promoter) and wild-type controls were injured mechanically with an epon resin probe. After 7 and 14 d, a progressive increase in medial area was seen in both SMP8-IGF-I and wild-type mice, but they were not significantly different from each other. However, by 14 d there was a more than 4-fold increase in neointimal area in transgenic vs. wild-type. The intima/media ratios were also strikingly increased at 14 d in the IGF-I-overexpressing animals. The mitotic index, determined in animals injected daily with bromodeoxyuridine for 3 d before death, was markedly elevated in both the media and neointima 7 d after injury in SMP8-IGF-I mice, but the effect had subsided by 14 d. Despite a higher rate of cell division, the relative increase in medial area was less in the SMP8-IGF-I mice than in wild-type mice at both 7 and 14 d, consistent with a stimulation of cell migration to the neointima. The experiments reported here provide compelling evidence that paracrine expression of IGF-I is a powerful stimulus for smooth muscle cell proliferation and migration in vivo.

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