Pathomechanisms of choroidal neovascularisation and oxidative stress

脉络膜新生血管（CNV）是渗出性年龄相关性黄斑变性（AMD）的关键过程，AMD是西方世界老年人失明的主要原因。在CNV中，源自脉络膜循环的新血管侵入Bruch膜并在视网膜色素上皮（RPE）下扩散。脉络膜内皮细胞（CEC）受到刺激而迁移、增殖和侵入周围组织。虽然CNV发展的主要刺激因素尚不清楚，但CEC的刺激可能与RPE细胞功能的改变有关。由活性氧（ROS）引起的氧化应激与多种年龄相关疾病有关，被认为是导致CNV的病理学改变的重要机制。已经表明AMD伴随着缺乏抗氧化剂，导致氧化应激升高。最近的一项研究（AREDS，年龄相关性眼病研究）的结果强烈表明，饮食补充抗氧化剂和锌可以有益于AMD患者预防进展为晚期AMD。CEC和RPE细胞被认为是参与AMD发病机制的最重要细胞。我们推测氧化应激对CNV相关的CEC和RPE细胞有直接和间接的影响，导致血管生成过程上调。为了证实这一假设，我们的研究目的是探讨氧化应激在CNV发病机制中的作用。详细地说，我们将把我们的研究重点放在氧化应激的细胞效应上，作为直接暴露于氧化剂的结果，或者通过释放RPE相关的可溶性因子间接介导。我们建议研究氧化应激对选定的血管生成相关的细胞因子，趋化因子和基质金属蛋白酶的表达的影响，并确定CEC增殖/活力，发芽，迁移和管形成在这种条件下。此外，还将研究氧化应激对CEC和RPE细胞共培养的影响。

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.