Growth factors in age-related macular degeneration: pathogenic and therapeutic implications

Abstract

Purpose: To investigate the role of growth factors in choroidal neovascularization in humans with age-related macular degeneration (ARMD) and in rats with choroidal neovascularization produced by krypton laser photocoagulation.

Methods: Autoradiography using 3H-thymidine in laser-treated rats. Light- and electron-microscopic immunocytochemistry using antibodies to several different growth factors and to the fibroblast growth factor (FGF) receptor. Tissues studied included the retinas of rats that had received krypton red laser photocoagulation, which induces formation of choroidal neovascularization 6-8 weeks after laser treatment, choroidal neovascular membranes (CNVMs) removed surgically from humans with ARMD and whole human eyes obtained postmortem with macular choroidal neovascular lesions from ARMD.

Results: Nuclei of retinal pigment epithelium (RPE) and choriocapillary cells in laser-treated rats were labeled with 3H-thymidine up to 80 days after photocoagulation, maximally at 2-7 days after laser treatment. At all intervals, RPE cells in treated areas immunolabeled for aFGF and bFGF. Labeling was strongest within lysosomes. RPE cells in untreated regions did not immunolabel for growth factors. RPE cells from CNVMs in the maculas of humans with ARMD also immunolabeled for aFGF and bFGF. Some choriocapillary endothelial cells in human CNVMs became labeled in a regular array along their anteluminal and luminal plasma membranes with anti-bFGF antibodies and, in a similar pattern, with antibodies to the FGF receptor. Finally, serial sections from some CNVMs in ARMD patients were immunostained alternately for bFGF and for vascular endothelial growth factor (VEGF). RPE cells and choriocapillary endothelial cells in these membranes immunostained for VEGF. Many immunostained for both bFGF and VEGF. In whole human eyes with macular CNVMs RPE cells in regions of normal retina did not immunostain for these growth factors.

Conclusions: Several growth factors are not expressed at detectable levels by immunocytochemistry in normal RPE cells in rats or humans but do appear following photocoagulation or the development of CNVMs in ARMD. This suggests that these growth factors have a pathogenic role in choroidal neovascularization. Possibly, bFGF and VEGF act synergistically to accelerate neovascularization. The up-regulation of VEGF in CNVMs is of special interest because up-regulation of this growth factor in other systems appears to be stimulated by tissue hypoxia. Till now, hypoxia has not been considered a major pathogenic agent in the development of CNVMs in ARMD or other macular diseases.