Balloon catheter vascular injury of the alloxan-induced diabetic rabbit: The role of insulin-like growth factor-1

Neointimal thickening following catheter injury is characterized, in part, by growth factor-induced vascular smooth muscle cell (VSMC) proliferation. It was hypothesized that a reduction in serum insulin-like growth factor-1 (IGF-1), characteristic of chemically-induced diabetes, would result in dec reased VSMC proliferation and attenuate neointimal thickening. It was found that alloxan-treated New Zealand White rabbits exhibit varying degrees of glycemia. Rabbits classified as diabetic (glucose greater than or equal to 400 mg/dL) had significantly decreased serum concentration of IGF-1 (87.4 /- 14 nmol/L vs. 170 +/- 14 nmol/L) and significantly decreased intimal/med ial (I/M) ratios 2, 4, and 8 weeks after aortic injury compared to euglycem ic rabbits (13.7 +/- 2, 21.1 +/- 2, 32.4 +/- 3 in euglycemics and 6.6 +/- 1 , 14 +/- 2, 19 +/- 5 in diabetics, respectively). The I/M for high hypergly cemic animals (glucose 286-399 mg/dL) was comparable to diabetic animals ye t their serum IGF-1 levels were normal rather than depressed. Vascular IGF- 1 content similarly increased upon injury in both diabetic and euglycemic a nimals. In diabetic animals, proliferating cell nuclear antigen (PCNA) immu nostaining was present by day 1 peaked by day 5 and returned to control by day 14. In euglycemic animals, staining by day 1 continued to increase thro ugh day 14. A similar increase in mitogen-activated protein kinase (MAPK) a ctivity occurred from day 1 through day 5 in both diabetic and euglycemic a nimals. This is the first demonstration of an association between MAPK acti vity and VSMC proliferation following vascular injury in diabetic animals a s previously reported in euglycemic animals. In conclusion, this study prov ides evidence against a direct effect of IGF-1 in the reduction in neointim al thickening, VSMC proliferation, and MAPK activity upon catheter injury i n chemically-induced diabetic rabbits.