Department of Biosciences and Territory, University of Molise, Pesche, Italy.
Department of Sense Organs, University of Rome "La Sapienza", Rome, Italy.
J Cell Physiol. 2019 Aug;234(10):18297-18307. doi: 10.1002/jcp.28462. Epub 2019 Mar 19.
This study sought to evaluate the prospective role exerted by vascular endothelial growth factor (VEGF) in the modulation of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) signalling pathways in the rabbit retina. To reach this aim, the anti-VEGF agents aflibercept and ranibizumab were used as a pharmacological approach to evaluate the putative consequences elicited by VEGF inhibition on neurotrophin signalling. VEGF inhibition determined a marked imbalance in proneurotrophin expression, a significant reduction in TrkA and TrkB phosphorylation states and a decrease in the pan-neurotrophin receptor p75. Importantly, VEGF blockade also caused a strong increase in cleaved caspase-3, beclin-1 and lipidated LC3. The effects were more pronounced in the aflibercept group when compared with ranibizumab-treated rabbits, particularly 1 week after injection. This study demonstrates that VEGF exerts pivotal physiological roles in regulating NGF and BDNF pathways in the retina, as its inhibition by anti-VEGF agents deeply impacts neurotrophin homeostasis. These events are accompanied by a sustained induction of apoptotic and autophagic markers, suggesting that anti-VEGF-dependent impairments in neurotrophin signalling could be responsible for the activation of retinal cell death pathways.
本研究旨在评估血管内皮生长因子（VEGF）在调节兔视网膜神经生长因子（NGF）和脑源性神经营养因子（BDNF）信号通路中的预期作用。为此，使用抗 VEGF 药物阿柏西普（aflibercept）和雷珠单抗（ranibizumab）作为药理学方法，评估 VEGF 抑制对神经营养因子信号的潜在影响。VEGF 抑制导致前神经生长因子表达明显失衡，TrkA 和 TrkB 磷酸化状态显著降低，泛神经生长因子受体 p75 减少。重要的是，VEGF 阻断还导致裂解型 caspase-3、beclin-1 和脂化 LC3 的大量增加。与雷珠单抗治疗的兔子相比，阿柏西普组的效果更为明显，特别是在注射后 1 周。本研究表明，VEGF 在调节视网膜中 NGF 和 BDNF 通路方面发挥着关键的生理作用，其通过抗 VEGF 药物的抑制会严重影响神经营养因子的平衡。这些事件伴随着持续诱导的凋亡和自噬标志物，表明抗 VEGF 依赖性的神经营养因子信号损伤可能导致视网膜细胞死亡途径的激活。
