School of Life Sciences, Faculty of Science and Engineering, Anglia Ruskin University, Cambridge, UK.
Vision and Eye Research Institute, Faculty of Health, Education, Medicine and Social Care, Anglia Ruskin University, Cambridge, UK.
Exp Eye Res. 2020 Aug;197:108104. doi: 10.1016/j.exer.2020.108104. Epub 2020 Jun 6.
Age-related macular degeneration (AMD) and proliferative diabetic retinopathy (DR) are two of the most common and severe causes of vision loss in the population. Both conditions are associated with excessive levels of vascular endothelial growth factor (VEGF) in the eye which results in an increase in the formation of new blood vessels through a process called neovascularisation. As such, anti-VEGF therapies are currently utilised as a treatment for patients with AMD however they are associated with painful administration of injections and potential degeneration of healthy endothelium. There is therefore growing interest in alternate treatment options to reduce neovascularisation in the eye. The use of carotenoids, lutein (L) and zeaxanthin (Z), has been shown to improve vision loss parameters in patients with AMD, however the underlying mechanisms are not well-understood. We studied the impact of these compounds on neovascularisation processes using an in vitro cell model of the retinal microvascular endothelium. Our findings show that L and Z reduced VEGF-induced tube formation whilst, in combination (5:1 ratio), the compounds significantly blocked VEGF-induced neovascularisation. The carotenoids, individually and in combination, reduced VEGF-induced oxidative stress concomitant with increased activity of the NADPH oxidase, Nox4. We further demonstrated that the Nox4 inhibitor, GLX7013114, attenuated the protective effect of L and Z. Taken together, these findings indicate the protective effect of the carotenoids, L and Z, in reducing VEGF-mediated neovascularisation via a Nox4-dependent pathway. These studies implicate the potential for these compounds to be used as a therapeutic approach for patients suffering from AMD and proliferative DR.
年龄相关性黄斑变性 (AMD) 和增生性糖尿病视网膜病变 (DR) 是人群中导致视力丧失的两个最常见和最严重的原因。这两种情况都与眼睛中血管内皮生长因子 (VEGF) 水平过高有关，这导致通过新生血管形成过程增加新血管的形成。因此，抗 VEGF 疗法目前被用作 AMD 患者的治疗方法，但它们与注射疼痛和健康内皮潜在退化有关。因此，人们越来越关注替代治疗方案，以减少眼睛中的新生血管形成。类胡萝卜素、叶黄素 (L) 和玉米黄质 (Z) 的使用已被证明可改善 AMD 患者的视力丧失参数，但潜在机制尚不清楚。我们使用视网膜微血管内皮细胞的体外细胞模型研究了这些化合物对新生血管形成过程的影响。我们的研究结果表明，L 和 Z 可减少 VEGF 诱导的管形成，而在组合 (5:1 比例) 下，这些化合物可显著阻断 VEGF 诱导的新生血管形成。类胡萝卜素单独和组合使用均可减少 VEGF 诱导的氧化应激，同时 NADPH 氧化酶 Nox4 的活性增加。我们进一步证明，Nox4 抑制剂 GLX7013114 可减弱 L 和 Z 的保护作用。综上所述，这些发现表明，类胡萝卜素、L 和 Z 通过 Nox4 依赖途径减少 VEGF 介导的新生血管形成具有保护作用。这些研究表明，这些化合物有可能被用作 AMD 和增生性 DR 患者的治疗方法。
