Exposure of vascular allografts to insulin-like growth factor-I (IGF-I) increases vascular expression of IGF-I ligand and receptor protein and accelerates arteriosclerosis in rats.
BACKGROUND
Accelerated arteriosclerosis limits the survival of transplanted hearts. We hypothesized that insulin-like growth factor-I (IGF-I) is crucial in accelerating transplant arteriosclerosis. Recently, we reported that exposure to IGF-I prior to transplantation accelerates transplant arteriosclerosis in the rat aorta allograft model. Here, we studied the mechanism whereby IGF-I exposure accelerates transplant arteriosclerosis.


METHODS
The abdominal aorta was harvested from male Brown Norway rats and exposed to 0, 200, or 500 ng/ml of IGF-I at 37 degrees C for 30 min prior to transplantation to the abdominal position of male Lewis rats. The allografts were harvested 14 days later and processed for immunohistochemical staining for alpha-actin, growth factors (IGF-I, IGF-I receptor, platelet-derived growth factor-BB, and basic fibroblast growth factor), and immunological markers (major histocompatibility complex class II antigen, macrophage, and CD4- and CD8-positive T cells).


RESULTS
By 14 days, the ex vivo IGF-I donor aorta treatment with IGF-I increased in a concentration-dependent manner the expression of IGF-I and IGF-I receptor in both the intima and the adventitia. In contrast, the expression of platelet-derived growth factor-BB was decreased in a concentration-dependent manner in the intima while basic fibroblast growth factor remained unchanged. The cell-mediated immune response was not affected by IGF-I at 14 days after transplantation, which suggests that the immune events associated with acceleration of transplant arteriosclerosis may occur at an earlier time.


CONCLUSIONS
Acceleration of transplant arteriosclerosis by exposure to IGF-I is associated with increased IGF-I ligand and receptor expression in the allograft vascular wall. These data further suggest that IGF-I may be a major factor in mediating graft arteriosclerosis.
Motomura
N
N
Department of Surgery, Georgetown University Medical Center, Washington, DC 20007, USA.
Lou
H
H
Orskov
H
H
Ramwell
P W
PW
Foegh
M L
ML
D000199:Actins / Q000032:analysis / Q000096:biosynthesis; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation*; D001161:Arteriosclerosis / Q000473:pathology*; D000077214:Becaplermin; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000097:blood; D018969:Insulin-Like Growth Factor Binding Proteins / Q000096:biosynthesis / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis*; D013997:Time Factors; D014184:Transplantation, Homologous; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology / Q000637:transplantation
D000199:Actins; D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D018974:Insulin-Like Growth Factor Binding Protein 4; D018969:Insulin-Like Growth Factor Binding Proteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D016222:Fibroblast Growth Factor 2; D000077214:Becaplermin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1