UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, City Road, London EC1V 2PD, UK.
Development. 2018 Apr 25;145(8):dev157511. doi: 10.1242/dev.157511.
In the adult central nervous system, endothelial and neuronal cells engage in tight cross-talk as key components of the so-called neurovascular unit. Impairment of this important relationship adversely affects tissue homeostasis, as observed in neurodegenerative conditions including Alzheimer's and Parkinson's disease. In development, the influence of neuroprogenitor cells on angiogenesis is poorly understood. Here, we show in mouse that these cells interact intimately with the growing retinal vascular network, and we identify a novel regulatory mechanism of vasculature development mediated by hypoxia-inducible factor 2a (Hif2a). By gene excision, we show that Hif2a in retinal neuroprogenitor cells upregulates the expression of the pro-angiogenic mediators vascular endothelial growth factor and erythropoietin, whereas it locally downregulates the angiogenesis inhibitor endostatin. Importantly, absence of in retinal neuroprogenitor cells causes a marked reduction of proliferating endothelial cells at the angiogenic front. This results in delayed retinal vascular development, fewer major retinal vessels and reduced density of the peripheral deep retinal vascular plexus. Our findings demonstrate that retinal neuroprogenitor cells are a crucial component of the developing neurovascular unit.
在成人中枢神经系统中，内皮细胞和神经元细胞作为所谓的神经血管单元的关键组成部分进行紧密的相互交流。这种重要关系的损害会对组织稳态产生不利影响，如在包括阿尔茨海默病和帕金森病在内的神经退行性疾病中观察到的那样。在发育过程中，神经祖细胞对血管生成的影响知之甚少。在这里，我们在小鼠中表明，这些细胞与不断生长的视网膜血管网络密切相互作用，并且我们确定了由缺氧诱导因子 2a（Hif2a）介导的血管发育的新调节机制。通过基因缺失，我们表明视网膜神经祖细胞中的 Hif2a 上调了血管内皮生长因子和促红细胞生成素等促血管生成介质的表达，而局部下调了血管生成抑制剂内皮抑素的表达。重要的是，视网膜神经祖细胞中的缺失会导致血管生成前沿处增殖的内皮细胞明显减少。这导致视网膜血管发育延迟，主要视网膜血管减少，周边深层视网膜血管丛密度降低。我们的研究结果表明，视网膜神经祖细胞是发育中的神经血管单元的重要组成部分。
