Pathomechanisms of choroidal neovascularisation and oxidative stress

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Choroidal neovascularization (CNV) is a key process in exsudative age-related macular degeneration (AMD), the leading cause of blindness in the elderly of the western world. In CNV, new vessels originated from choroidal circulation invade through Bruch's membrane and spread out under the retinal pigment epithelium (RPE). Choroidal endothelial cells (CEC) are stimulated to migrate, proliferate, and invade surrounding tissues. Although the primary stimulus for the development of CNV is unknown, stimulation of CEC is probably related to altered RPE cell function. Oxidative stress caused by reactive oxygen species (ROS) has been implicated in several age-related disorders and is considered as an important mechanism involved in pathological alterations which may result in CNV. It has been suggested that AMD is accompanied by lack of antioxidants resulting in elevated oxidative stress. Results of a recent study (AREDS, age-related eye disease study) strongly suggest, that dietary supplementation of antioxidants and zinc can be beneficial for AMD patients in preventing progression to advanced AMD. CEC and RPE cells are discussed to be the most important cells involved in pathogenesis of AMD. We hypothesize that oxidative stress has direct and indirect effects on the CNV-related CEC and RPE cells, resulting in upregulated angiogenic processes. To corroborate this hypothesis the purpose of our study is to investigate the role of oxidative stress on processes involved in pathogenesis of CNV. In detail, we will focus our study on cellular effects of oxidative stress, as a consequence of direct exposure to oxidants, or mediated indirectly by release of RPE-associated soluble factors. We propose to study effects of oxidative stress on the expression of selected angiogenesis-related cytokines, chemokines, and matrix metalloproteinases and to determine CEC proliferation/viability, sprouting, migration, and tube formation under this condition. Also effects of oxidative stress on CEC and RPE cell coculture will be investigated.