PlGF and VEGF-A/PlGF heterodimer are crucial for recruitment and activation of immune cells during choroid neovascularization

Purpose. Recruitment and activation of inflammatory cells, such as retinal microglia/macrophages, in the sub-retinal space contribute significantly to the pathogenesis of age-related macular degeneration (AMD). This study aims to explore the functional role of vascular endothelial growth factor (VEGF-A), placental growth factor (PlGF) and VEGF-A/PlGF heterodimer in immune homeostasis and activation during pathological laser-induced choroidal neovascularization (CNV). Methods . To investigated these roles, we utilized the PlGF-DE knockin mouse model, which is the full functional knockout of PlGF. In this model, mice express a variant of PlGF, named PlGF-DE, that is unable to bind and activate VEGFR-1 but can still form heterodimer with VEGF-A. Results. Our findings demonstrate that, while there is no difference in healthy conditions, PlGF-DE-Ki mice exhibit decreased microglia reactivity and reduced recruitment of both microglia and monocyte-macrophages, compared to wild-type mice during laser-induced CNV. This impairment is associated with a reduction in VEGF receptor 1 (VEGFR-1) phosphorylation in the retinae of PlGF-DE-Ki mice compared to C57Bl6/J mice. Corroborating these data, intravitreal delivery of PlGF or VEGF-A/PlGF heterodimer in PlGF-DE-Ki mice rescued the immune cell response at the early phase of CNV compared to VEGF-A delivery. Conclusions. In summary, our study suggests that targeting PlGF and the VEGF-A/PlGF heterodimer, thereby preventing VEGFR-1 activation, could represents a potential therapeutic approach for the management of inflammatory processes in diseases such as AMD.