Influence of inflammatory mediators on RPE barrier function and choroidal neovascularization

白细胞与AMD的发病机制有关，因为它们在人类和动物模型中的时空分布与树突性CNV相关。促血管生成生长因子VEGF诱导血管内皮细胞间粘附分子1 （ICAM - 1）的表达，调控白细胞对内皮细胞的粘附。这些系统是交织在一起的，因为白细胞拥有对VEGF的受体并响应其迁移，也可以产生和释放VEGF。目前认为病理性血管生成是两个生长因子家族：VEGF/Flt-1系统和血管生成素1,2 /Tie1,2系统失衡的表现。Ang-1稳定血管，而Ang-2与VEGF联合促进血管重塑，在缺乏VEGF时促进血管退化。Fas-FasL系统已被证明通过减少内皮发芽发挥抑制作用。关于炎症与脉络膜新生血管形成的次要原因的主要作用的讨论仍未解决，但有证据表明，RPE细胞通过表达促血管生成和抗血管生成分子可能起核心作用。我们使用两个转基因小鼠模型来研究这些分子在RPE细胞中的表达是否足以调节导致脉络膜新生血管的血管生成过程，或者是否有或没有炎症刺激的Bruch膜破裂是脉络膜新生血管形成的先决条件。这些实验可能揭示脉络膜新生血管的发病机制，并有助于寻找因果治疗策略。

Leukocytes have been implicated in the pathogenesis of AMD because their spatiotemporal distribution correlates with arborizing CNV in humans and in animal models. The proangiogenic growth factor VEGF induces the expression of intercellular adhesion molecule 1 (ICAM 1) on vascular endothelium and regulates leukocyte adhesion to endothelial cells. These systems are intertwined as leukocytes, which possess receptors for and migrate in response to VEGF, can also produce and release VEGF. It is currently believed that pathological angiogenesis is a manifestation of an imbalance between two growth factor families: the VEGF/Flt-1 system and the angiopoietin1, 2/Tie1,2 system. Ang-1 stabilizes vessels, whhereas Ang-2 promotes vascular remodeling in combination with VEGF and vessel regression in the absence of VEGF. The Fas-FasL system has been demonstrated to exert an inhibitory role by reducing endothelial sprouting. The discussion of a primary role of inflammation versus a secondary cause of choroidal neovascularization is stillnot solved, however there is evidence that the RPE cells via expression of pro- and anti-angiogenic molecules might play a central role. we use two transgenic mouse models to investigate whether the expression of those molecules within RPE cells is sufficient to regulate the angiogenic process that leads to choroidal neovascularization or whether ruptures of Bruch's membrane with or without inflammatory stimuli are prerequisite for the initiation of choroidal neovascularization. These experiments might shed light on the pathogenesis of choroidal neovascularization and help in the search for causal therapeutic strategies.