Responses to vascular injury in the alloxan-induced diabetic rabbit
Description
The cascade of pathophysiological events that ensue in response to vascular injury is analogous to generalized wound healing. Vascular injury in which the endothelial cell layer is denuded and the underlying vascular smooth muscle cell (VSMC) layer is disrupted results in an expansion of the neointima. The phases of the healing process are controlled in large part by growth factors released at the site of injury Once cells are made competent, progression factors such as insulin-like growth factor-1 (IGF-1) act to promote cells through the cell cycle and thus, allow for a full proliferative response. It was hypothesized that a reduction in serum IGF-1, characteristic of chemically-induced diabetes, would contribute to an impaired wound healing response such that VSMC proliferation, migration and ultimately, neointimal thickening in response to vascular injury would be attenuated Delayed reendothelialization following vascular injury has been suggested to have a permissive impact on VSMC proliferation. This is illustrated by the finding that in areas in which the endothelial lining rapidly regenerates following injury, neointimal thickening is less marked than areas where regeneration occurs later. It was also hypothesized that endothelial cell regrowth, morphology, and endothelium-dependent vasoreactivity following catheter injury are improved by the diabetic state and account, in part, for the decreased mitogenic response and the attenuated neointimal thickening in response to vascular injury It was found that alloxan-treated New Zealand White rabbits classified as diabetic (glucose ≥ 400mg/dL) had significantly decreased serum IGF-1 levels compared to untreated, euglycemic rabbits. Diabetic rabbits also had decreased I/M ratios (area of the intima divided by the area of the media multiplied by 100) 2, 4, and 8 weeks after aortic injury compared to euglycemic rabbits. The I/M for high hyperglycemic rabbits (glucose = 286--399 mg/dL) was comparable to diabetic animals yet their IGF-1 levels were not significantly different from control. Vascular IGF-1 content was similarly increased following catheter injury between diabetic and euglycemic rabbits Two weeks after catheter injury the percent of endothelial cell regrowth was significantly increased in diabetic animals compared to euglycemic animals In conclusion, this study provides evidence against a direct effect of IGF-1 in the impaired wound healing, VSMC proliferation and migration, and MAPK activity following balloon catheter injury of the alloxan-induced diabetic rabbit. Further, these results show that endothelial cell regrowth and morphology in diabetic rabbits is improved, however, the restoration of endothelium-dependent vasoreactivity is not. (Abstract shortened by UMI.)