R 205Factors inducing angiogenesis in age-related macular degeneration
The principal cause for the loss of vision in age-related macular degeneration (AMD) is choroidal neovascularization. Changes in the composition of Bruchs membrane in combination with the detachment of the retinal pigment epithelium (RPE) establish a metabolic situation comparable to hypoxia. As a result, the development of new blood vessels is induced by mechanisms which are not fully understood. However, many recently published observations provide the basis for new approaches to understand and to develop strategies to prevent this process. Angiogenic factors are secreted by the RPE which starts to proliferate and dedifferentiate. The following growth factors have been found in neovascular membranes and seem to be involved in the stimulation of endothelial cell proliferation: transforming growth factor b 1 (TGF-b 1), vascular endothelial growth factor (VEGF), plateled-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF). The secretion by the RPE is auto- and paracrinially stimulated by growth factors and by changes in the microenvironment of RPE cells. For example, insulin-like growth factor (IGF) is secreted by Müller cells and stimulates the secretion of VEGF. The RPE secretes TGF-b 1 which leads to the autocrinially stimulated secretion of PDGF. Advanced glycation endproducts (AGEs) are known to stimulate the secretion of VEGF by the RPE in vitro and have been found in abundance in proliferative membranes. The secretion by the RPE might also be changed by extracellular matrix proteins. Only vitronectin and not the characteristic proteins of Bruchs membrane has been found in drusen. The vitronectin-dependent stimulation of integrins induces the secretion of VEGF by the RPE. Furthermore, fas (CD95)-dependent control of apoptosis in endothelial cells seems to control angiogenesis in age-related macular degeneration. New vessels were found to be fas positive, and surrounding RPE cells express fas ligand. In summary, the RPE plays a key role in AMD not only by initiating the disease but also by secretion of angiogenic factors. For this process new extracellular signal transduction mechanisms have been found.
Institut für Klinische Physiologie, Universitätsklinikum Benjamin Franklin der Freien Universität Berlin; Hindenbrugdamm 30, 12200 Berlin