Intravitreal VEGF and bFGF produce florid retinal neovascularization and hemorrhage in the rabbit.
OBJECTIVE
Vascular endothelial growth factor (VEGF) causes widespread retinal vascular dilation, produces breakdown of the blood-retinal barrier, and is implicated in ocular neovascularization (NV). Basic fibroblast growth factor (bFGF) also has been implicated in the production of ocular NV. This study was performed to investigate the ability of simultaneous sustained intravitreal release of both VEGF and bFGF to induce robust retinal NV in the rabbit.


METHODS
Intravitreal implantation of sustained-release Hydron polymeric pellets containing both 20 microg of VEGF and 20 microg of bFGF was performed on adult male Dutch belted rabbits. In other animals either 20 microg or 50 microg bFGF-containing pellets was implanted intravitreally; also, either 20 microg VEGF or 50 microg VEGF-containing pellets was implanted. Control rabbits received either blank polymeric pellets or a pellet containing 30 microg bovine serum albumin. Eyes were examined by indirect ophthalmoscopy after surgery at 24 hrs, 48 hrs, 4 days, 7 days, 14 days, 21 days, and 28 days. Findings were documented by color fundus photography and fluorescein angiography (FA). Eyes were enucleated and prepared for histologic analysis at 28 days following intravitreal implantation of the VEGF/bFGF-containing pellets.


RESULTS
In all eyes implanted with VEGF/bFGF pellets, dilation and tortuosity of existing blood vessels were observed within 48 hrs after pellet implantation. The progression of retinal vascular changes was rapid and occurred over the entire optic disk and medullary rays between 4 and 7 days. Hemorrhage occurred as early as 14 days after VEGF/bFGF pellet implantation. In eyes with massive hemorrhage, total traction retinal detachment developed after the second week. The presence of abnormal tissues at the vitreo-retinal interface within 28 days was demonstrated by light microscopy while FA showed profuse leakage of dye from anomalous vessels within the first week. Neither bFGF-exposed eyes nor control eyes showed any vascular changes. Eyes that received only VEGF-containing pellets exhibited tortuosity of existing vessels, but neither hemorrhaging nor retinal detachment occurred.


CONCLUSIONS
These results demonstrate that retinal vascular changes leading to hemorrhaging is produced rapidly in the rabbit by simultaneous intravitreal release of both VEGF and bFGF. Understanding how these growth factors induce retinal NV may suggest novel therapeutic treatment strategies.
Wong
C G
CG
Department of Ophthalmology, University of California Irvine College of Medicine, Irvine, California 92697, USA. cgwong@uci.edu
Rich
K A
KA
Liaw
L H
LH
Hsu
H T
HT
Berns
M W
MW
D000818:Animals; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D004343:Drug Implants; D016228:Endothelial Growth Factors / Q000633:toxicity*; D016222:Fibroblast Growth Factor 2 / Q000633:toxicity*; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D008222:Lymphokines / Q000633:toxicity*; D008297:Male; D009887:Ophthalmoscopy; D011817:Rabbits; D012163:Retinal Detachment / Q000139:chemically induced / Q000473:pathology; D012166:Retinal Hemorrhage / Q000139:chemically induced* / Q000473:pathology; D015861:Retinal Neovascularization / Q000139:chemically induced* / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014822:Vitreous Body
D003692:Delayed-Action Preparations; D004338:Drug Combinations; D004343:Drug Implants; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2