Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
Prog Retin Eye Res. 2021 Sep;84:100954. doi: 10.1016/j.preteyeres.2021.100954. Epub 2021 Feb 25.
Five vascular endothelial growth factor receptor (VEGFR) ligands (VEGF-A, -B, -C, -D, and placental growth factor [PlGF]) constitute the VEGF family. VEGF-A binds VEGF receptors 1 and 2 (VEGFR1/2), whereas VEGF-B and PlGF only bind VEGFR1. Although much research has been conducted on VEGFR2 to elucidate its key role in retinal diseases, recent efforts have shown the importance and involvement of VEGFR1 and its family of ligands in angiogenesis, vascular permeability, and microinflammatory cascades within the retina. Expression of VEGFR1 depends on the microenvironment, is differentially regulated under hypoxic and inflammatory conditions, and it has been detected in retinal and choroidal endothelial cells, pericytes, retinal and choroidal mononuclear phagocytes (including microglia), Müller cells, photoreceptor cells, and the retinal pigment epithelium. Whilst the VEGF-A decoy function of VEGFR1 is well established, consequences of its direct signaling are less clear. VEGFR1 activation can affect vascular permeability and induce macrophage and microglia production of proinflammatory and proangiogenic mediators. However the ability of the VEGFR1 ligands (VEGF-A, PlGF, and VEGF-B) to compete against each other for receptor binding and to heterodimerize complicates our understanding of the relative contribution of VEGFR1 signaling alone toward the pathologic processes seen in diabetic retinopathy, retinal vascular occlusions, retinopathy of prematurity, and age-related macular degeneration. Clinically, anti-VEGF drugs have proven transformational in these pathologies and their impact on modulation of VEGFR1 signaling is still an opportunity-rich field for further research.
五种血管内皮生长因子受体（VEGFR）配体（VEGF-A、-B、-C、-D 和胎盘生长因子[PlGF]）构成了 VEGF 家族。VEGF-A 结合 VEGFR1 和 2（VEGFR1/2），而 VEGF-B 和 PlGF 仅结合 VEGFR1。尽管已经进行了大量关于 VEGFR2 的研究来阐明其在视网膜疾病中的关键作用，但最近的研究表明 VEGFR1 及其配体家族在血管生成、血管通透性和视网膜内微小炎症级联反应中的重要性和参与。VEGFR1 的表达取决于微环境，在缺氧和炎症条件下受到差异调节，并且已在视网膜和脉络膜内皮细胞、周细胞、视网膜和脉络膜单核吞噬细胞（包括小胶质细胞）、Müller 细胞、光感受器细胞和视网膜色素上皮中检测到。虽然 VEGFR1 的 VEGF-A 诱饵功能已经得到很好的证实，但它的直接信号传导的后果尚不清楚。VEGFR1 的激活可以影响血管通透性，并诱导巨噬细胞和小胶质细胞产生促炎和促血管生成介质。然而，VEGFR1 配体（VEGF-A、PlGF 和 VEGF-B）相互竞争受体结合并形成异二聚体的能力使我们对 VEGFR1 信号传导单独对糖尿病性视网膜病变、视网膜血管阻塞、早产儿视网膜病变和年龄相关性黄斑变性中所见的病理过程的相对贡献的理解变得复杂。临床上，抗 VEGF 药物已被证明在这些疾病中具有变革性，它们对 VEGFR1 信号传导的调节仍然是一个充满机遇的研究领域。
