Unraveling the impact of VEGF signaling in astrocytes during retinal angiogenesis

• Applicant: Professorin Dr. Barbara Braunger
• Subject Area: Ophthalmology ; Anatomy and Physiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568173771

Retinal angiogenesis in mice starts after birth with the migration of astrocytes from the optic nerve into the retina. These astrocytes secrete factors such as vascular endothelial growth factor (VEGF) to recruit endothelial cells, which form the superficial vascular plexus along the VEGF gradient. From there, vessels sprout deeper to form the intermediate and deep vascular plexus of the retina. Our preliminary data show that postnatal deletion of the VEGF signaling pathway in the murine retina leads to an avascular, hypoxic retina. Remarkably, the retina of our mouse model shows significantly more astrocytes despite being avascular. Since astrocytes were also affected by the deletion of VEGF signaling, we hypothesize that during retinal angiogenesis, the VEGF signaling pathway and/or hypoxia are essential not only for endothelial cells but also for astrocytes. To further elucidate the effects of the VEGF signaling pathway on different cell populations during retinal angiogenesis and in particularly for astrocytes, we propose a broad range of in vivo and in vitro experiments: By way of single-cell RNA sequencing of VEGF signaling depleted versus control retinae, we will analyze the effects of the VEGF signaling pathway on the individual retinal cell populations and their interactions during retinal angiogenesis. Using primary murine optic nerve astrocytes, we will distinguish between VEGF- and hypoxia-mediated effects on their proliferation, migration, and maturation, and capture the underlying transcriptional changes by RNAsequencing. Additionally, we will specifically delete the VEGF receptor 2 in astrocytes in vivo to examine its influence on their proliferation, migration, and maturation. Here, we will also study whether deletion of VEGFR2 in astrocytes will hamper the process of retinal angiogenesis and retinal function. Finally, we will employ a bioinformatic translational approach to compare our data with existing datasets from patients with age-related macular degeneration, Alzheimer’s disease, and multiple sclerosis to identify transferable signaling pathways and disease-relevant cell populations. Our analyses of the impact of VEGF signaling pathway on individual retinal cell populations during retinal angiogenesis, their interactions, and particularly our focus on retinal astrocytes will provide valuable insights into the molecular interplay during retinal angiogenesis. Given that an avascular, hypoxic retina resembles the phenotype of retinopathy of prematurity (ROP), a severe vision-threatening condition, our findings are directly therapeutically relevant, especially since ROP is mostly treated with intraocular anti-VEGF injections. Thus our findings may reveal future treatment options for ROP and could also be applicable to other diseases characterized by vascular proliferation or glial cell involvement, both in the eye and beyond.

• DFG Programme: Research Grants