Inhibition of vascular endothelial growth factor reduces scar formation after glaucoma filtration surgery.
OBJECTIVE
Filtration failure due to excessive postoperative scarring remains a major problem after glaucoma surgery. The authors have investigated whether glaucoma and filtration surgery are associated with increased levels of vascular endothelial growth factor (VEGF), and whether a humanized monoclonal antibody against VEGF, bevacizumab, can reduce postoperative scar formation and improve surgical outcome.


METHODS
The levels of VEGF in samples of aqueous humor were measured by ELISA. The expression of the VEGF receptors Flt-1 and KDR was analyzed in cultured Tenon fibroblasts by real-time RT-PCR and Western blotting. The effect of VEGF and bevacizumab on Tenon fibroblasts in vitro was determined using a proliferation assay. The in vivo effect of the antibody was investigated in a rabbit model of trabeculectomy by measuring the intraocular pressure (IOP) and bleb area, and by immunohistological analysis of angiogenesis, inflammation, and fibrosis.


RESULTS
VEGF levels were increased significantly in the aqueous humor of glaucoma patients and rabbits that had undergone surgery. Both VEGF receptors were expressed on Tenon fibroblasts. Fibroblast proliferation in vitro was stimulated by delivery of VEGF, and was inhibited by administration of bevacizumab. The antibody also reduced angiogenesis and collagen deposition significantly, and improved the outcome of glaucoma surgery in rabbits.


CONCLUSIONS
VEGF was upregulated in the aqueous humor of glaucoma patients and in the rabbit model, and it stimulated fibroblast proliferation in vitro. This suggests that it is involved in the scarring process after filtration surgery. Bevacizumab reduced the proliferation of fibroblasts in vitro and improved surgical outcome.
Li
Zhongqiu
Z
Laboratory of Ophthalmology, Catholic University Leuven, Leuven, Belgium.
Van Bergen
Tine
T
Van de Veire
Sara
S
Van de Vel
Isabelle
I
Moreau
Huberte
H
Dewerchin
Mieke
M
Maudgal
Prabhat C
PC
Zeyen
Thierry
T
Spileers
Werner
W
Moons
Lieve
L
Stalmans
Ingeborg
I
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000867:Anterior Chamber; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D001082:Aqueous Humor / Q000378:metabolism; D000068258:Bevacizumab; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002921:Cicatrix / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D003229:Conjunctival Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005902:Glaucoma, Open-Angle / Q000601:surgery*; D006801:Humans; D007267:Injections; D007429:Intraocular Pressure; D011183:Postoperative Complications; D011817:Rabbits; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014065:Tonometry, Ocular; D014130:Trabeculectomy; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2