Targeted overexpression of IGF-I in smooth muscle cells of transgenic mice enhances neointimal formation through increased proliferation and cell migration after intraarterial injury.
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 alpha-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.
Zhu
B
B
Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio 45267, USA.
Zhao
G
G
Witte
D P
DP
Hui
D Y
DY
Fagin
J A
JA
D000199:Actins / Q000378:metabolism; D000818:Animals; D020212:Carotid Artery Injuries / Q000473:pathology* / Q000503:physiopathology*; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects / Q000254:growth & development*
D000199:Actins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I