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

Department of Pathology and Laboratory Medicine (B.Z., D.Y.H.), Division of Endocrinology and Metabolism (G.Z., J.A.F.), University of Cincinnati, and Department of Pathology, Children’s Hospital Medical Center (D.P.W.), Cincinnati, Ohio 45267

Address all correspondence and requests for reprints to: James A. Fagin, M.D., Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, Vontz Center for Molecular Studies, 3125 Eden Avenue, Cincinnati, Ohio 45267. E-mail: faginja{at}uc.edu

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 -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.