Institute of Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, TU Dresden, Dresden, Germany.
Department of Ophthalmology, University Clinic Carl Gustav Carus, TU Dresden, Dresden, Germany.
J Cell Mol Med. 2019 Apr;23(4):2362-2371. doi: 10.1111/jcmm.14002. Epub 2019 Jan 24.
The mechanism underlying vasoproliferative retinopathies like retinopathy of prematurity (ROP) is hypoxia-triggered neovascularisation. Nerve growth factor (NGF), a neurotrophin supporting survival and differentiation of neuronal cells may also regulate endothelial cell functions. Here we studied the role of NGF in pathological retinal angiogenesis in the course of the ROP mouse model. Topical application of NGF enhanced while intraocular injections of anti-NGF neutralizing antibody reduced pathological retinal vascularization in mice subjected to the ROP model. The pro-angiogenic effect of NGF in the retina was mediated by inhibition of retinal endothelial cell apoptosis. In vitro, NGF decreased the intrinsic (mitochondria-dependent) apoptosis in hypoxia-treated human retinal microvascular endothelial cells and preserved the mitochondrial membrane potential. The anti-apoptotic effect of NGF was associated with increased BCL2 and reduced BAX, as well as with enhanced ERK and AKT phosphorylation, and was abolished by inhibition of the AKT pathway. Our findings reveal an anti-apoptotic role of NGF in the hypoxic retinal endothelium, which is involved in promoting pathological retinal vascularization, thereby pointing to NGF as a potential target for proliferative retinopathies.
血管增生性视网膜病变（ROP）的发病机制是缺氧诱导的新生血管形成，神经营养因子（NGF）是一种支持神经元细胞存活和分化的神经营养因子，也可能调节内皮细胞的功能。在此，我们研究了 NGF 在 ROP 小鼠模型中病理性视网膜血管生成过程中的作用。在 ROP 模型小鼠中，NGF 的局部应用增强了，而眼内注射抗 NGF 中和抗体则减少了病理性视网膜血管生成。NGF 在视网膜中的促血管生成作用是通过抑制视网膜内皮细胞凋亡来介导的。在体外，NGF 降低了缺氧处理的人视网膜微血管内皮细胞中的内在（线粒体依赖性）凋亡，并维持了线粒体膜电位。NGF 的抗凋亡作用与 BCL2 的增加和 BAX 的减少有关，以及 ERK 和 AKT 磷酸化的增强，而 AKT 途径的抑制则消除了这种作用。我们的研究结果揭示了 NGF 在缺氧性视网膜内皮细胞中的抗凋亡作用，它参与了促进病理性视网膜血管生成，从而表明 NGF 可能是增殖性视网膜病变的一个潜在靶点。
