Schlecht Anja, Leimbeck Sarah V, Jägle Herbert, Feuchtinger Annette, Tamm Ernst R, Braunger Barbara M
Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany.
Department of Ophthalmology, University Clinic Regensburg, Regensburg, Germany.
Am J Pathol. 2017 Nov;187(11):2570-2589. doi: 10.1016/j.ajpath.2017.06.018. Epub 2017 Aug 18.
The molecular pathogenesis of choroidal neovascularization (CNV), an angiogenic process that critically contributes to vision loss in age-related macular degeneration, is unclear. Herein, we analyzed the role of transforming growth factor (TGF)-β signaling for CNV formation by generating a series of mutant mouse models with induced conditional deletion of TGF-β signaling in the entire eye, the retinal pigment epithelium (RPE), or the vascular endothelium. Deletion of TGF-β signaling in the eye caused CNV, irrespectively if it was ablated in newborn or 3-week-old mice. Areas of CNV showed photoreceptor degeneration, multilayered RPE, basal lamina deposits, and accumulations of monocytes/macrophages. The changes progressed, leading to marked structural and functional alterations of the retina. Although the specific deletion of TGF-β signaling in the RPE caused no obvious changes, specific deletion in vascular endothelial cells caused CNV and a phenotype similar to that observed after the deletion in the entire eye. We conclude that impairment of TGF-β signaling in the vascular endothelium of the eye is sufficient to trigger CNV formation. Our findings highlight the importance of TGF-β signaling as a key player in the development of ocular neovascularization and indicate a fundamental role of TGF-β signaling in the pathogenesis of age-related macular degeneration.
脉络膜新生血管（CNV）是一种血管生成过程，在年龄相关性黄斑变性导致视力丧失中起关键作用，其分子发病机制尚不清楚。在此，我们通过构建一系列在全眼、视网膜色素上皮（RPE）或血管内皮中诱导条件性缺失转化生长因子（TGF）-β信号的突变小鼠模型，分析了TGF-β信号在CNV形成中的作用。在眼中缺失TGF-β信号会导致CNV，无论在新生小鼠还是3周龄小鼠中进行消融。CNV区域显示光感受器退化、RPE多层化、基底膜沉积以及单核细胞/巨噬细胞聚集。这些变化不断进展，导致视网膜出现明显的结构和功能改变。尽管在RPE中特异性缺失TGF-β信号未引起明显变化，但在血管内皮细胞中特异性缺失会导致CNV以及与在全眼中缺失后观察到的相似表型。我们得出结论，眼中血管内皮细胞中TGF-β信号受损足以触发CNV形成。我们的研究结果突出了TGF-β信号作为眼部新生血管形成关键参与者的重要性，并表明TGF-β信号在年龄相关性黄斑变性发病机制中起重要作用。
