Differential retinal angiogenic response to sustained intravitreal release of VEGF and bFGF in different pigmented rabbit breeds

Abstract

Purpose. To determine if two different breeds of pigmented rabbits can demonstrate differences in the degree of inducible angiogenesis within the retina. Methods. Non-biodegradable Hydron pellets approximately 1.5mm in diameter containing both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were implanted intravitreally over the optic disk of either Dutch belt rabbits or New Zealand White/Black satin cross rabbits. Control animals from both groups were implanted with blank Hydron pellets. Animals were examined periodically over a 30-day period following implantation. Results were documented by fundus photography and flourescein angiography. Stages of neovascularization (NV) were graded between +1 (preproliferative) and +4 (total NV) with +5 for NV complicated by hemorrhage and/or retinal detachment. Results. The angiogenic response in the retinas of pigmented NZW/Black satin cross rabbits (N = 5) following implantation of VEGF/bFGF-containing pellets varied extensively from the Dutch belt animals (N = 7). In the Dutch belt rabbits, grading of the angiogenic response demonstrated either +4 or +5 between day 20 and day 30 after implantation. In contrast, the NZW/Black satin cross animals gave a more muted response with a maximum grade of +2 following exposure to the same amount of VEGF and bFGF. Control eyes that received only blank pellets showed no evidence of retinal NV in either the Dutch belts (N = 5) or the NZW/Black satin cross rabbits (N = 5). Statistical analysis showed a significant interaction effect for breed and pellet type (F = 44.85 with 1df, p < 0.00005), indicating a difference between the breeds in the angiogenic response to the pellet. Moreover, both the NZW/BSC and Dutch belt rabbits displayed a significant increase in angiogenesis with the VEGF/bFGF pellet in comparison to the blank pellet (p = 0.037 and p < 0.00005, respectively). Conclusions. These studies indicate that two different breeds of pigmented rabbits exhibit different angiogenic responses to the same amount of both VEGF and bFGF. Florid retinal NV leading to hemorrhage, fibrovascular membrane formation, and traction retinal detachment occurred in the Dutch belt rabbits while tortuosity and dilatation of existing blood vessels with subsequent regression occurred in the NZW/ Black satin cross animals. Such differences in the angiogenic response may be due to differences in the genetic background of these animals. If genetic heteriogeneity exists for angiogenic responses, then understanding the genetic role in the regulation of angiogenesis will lead to the design of more effective anti-angiogenic agents and can provide predictive outcomes of individual responses to therapy.