VEGFR1 signaling in retinal angiogenesis and microinflammation

• Published in: Progress in retinal and eye research 2021-09, Vol.84, p.100954-100954, Article 100954
• Main Authors: Uemura, Akiyoshi, Fruttiger, Marcus, D'Amore, Patricia A., De Falco, Sandro, Joussen, Antonia M., Sennlaub, Florian, Brunck, Lynne R., Johnson, Kristian T., Lambrou, George N., Rittenhouse, Kay D., Langmann, Thomas
• Format: Article
• Language: English
• Subjects: Angiogenesis; Endothelial Cells; Humans; Inflammation - pathology; Life Sciences; Microinflammation; Neovascularization, Pathologic; Placenta Growth Factor; Placental growth factor (PlGF); Retina - pathology; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular endothelial growth factor receptor 1 (VEGFR1); Vascular Endothelial Growth Factor Receptor-1; Vascular endothelial growth factor-A (VEGF-A)
• ISSN: 1350-9462; 1873-1635; 1873-1635
• DOI: 10.1016/j.preteyeres.2021.100954

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. •VEGF-A, VEGF-B, PlGF and VEGFR1/R2 can form homodimers or heterodimers.•The complexity of VEGF family ligands and receptor interactions is underappreciated.•VEGFR1 and PlGF are involved in inflammatory pathways of retinal diseases.•A contribution of VEGFR1 to retinopathy via effects on inflammation is likely.•Clinical relevance of targeting both VEGF-A/PlGF vs VEGF-A needs further elucidation.