In diabetes mellitus, there is a problem of both premature atherosclerosis as well as impaired collateralization. Studies were performed using the rat corneal angiogenesis model as a surrogate for collateralization to determine the effect of diabetes mellitus on endothelin (ET)-1, ET-3, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8)-mediated angiogenesis. In an initial group of experiments, streptozotocin-induced diabetes resulted in impairment of ET-1-mediated angiogenesis from 69% to 32%, but was only impaired from 74% to 59% for ET-3. When rats were fluid-resuscitated, mortality fell, and the incidence of inhibition of angiogenesis decreased for ET-1, but was still at 47%. Inhibition of ET-3-mediated angiogenesis in fluid-resuscitated rats was essentially unaffected from 74% to 75%. Studies of VEGF and IL-8 in fluid-resuscitated rats demonstrated that VEGF-mediated angiogenesis was only inhibited from 49% to 45%, but there was inhibition of IL-8-mediated angiogenesis from 62% to 31%. We concluded that there may be two mechanisms by which ET-1-mediated corneal angiogenesis is inhibited: a decrease in intravascular volume and dynamic forces affecting angiogenesis, and a direct effect of diabetes on some aspect of cell growth or angiogenic process. Diabetes also appeared to inhibit IL-8-mediated angiogenesis, but had very little or no effect on ET-3- or VEGF-mediated angiogenesis.