Targeted overexpression of IGF-I in smooth muscle cells of transgenic miceenhances neointimal formation through increased proliferation and cell migration after intraarterial injury

The response of arterial smooth muscle cells to injury is governed by a com plex series of events. Significant among them is the paracrine production o f peptide growth factors. To determine the impact of local IGF-I gene expre ssion on vascular injury, the left carotid arteries of SMPS-IGF-I mice (in which IGF-l is selectively overexpressed in smooth muscle cells by means of a smooth muscle a-actin promoter) and wild-type controls were injured mech anically 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 we re 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 i n 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 r elative increase in medial area was less in the SMP8-IGF-I mice than in wil d-type mice at both 7 and 14 d, consistent with a stimulation of cell migra tion to the neointima. The experiments reported here provide compelling evi dence that paracrine expression of IGF-I is a powerful stimulus for smooth muscle cell proliferation and migration in vivo.