PROJECT SUMMARY Pericytes and myeloid cells cooperate with endothelium to orchestrate formation of a properly branched, functional vessel network that sustains retinal function and thereby enables vision. Disrupted communication between endothelium, pericytes and myeloid cells leads to excessive and pathological angiogenesis in ocular neovascular diseases (ONDs) such as advanced age-related macular degeneration and diabetic retinopathy that cause vision loss in millions of Americans. Excessive angiogenesis is currently treated by inhibition of a single factor VEGF that targets endothelial cells only. In this proposal we identify a novel SLIT2-ROBO1&2 ligand- receptor pathway that promotes retinal neovascularization through direct receptor signaling effects in pericytes and myeloid cells. By targeting pericytes and myeloid cells, ROBO inhibition in ONDs may confer additional benefit over VEGF inhibition of ECs alone. We will define the molecular basis of SLIT2-ROBO1&2 signaling and its biological role in pericytes and myeloid cells to uncover novel biology controlling retinal development and homeostasis that could be applied to OND prevention.

Narrative Angiogenesis in the developing retina requires communication between endothelial cells, pericytes and myeloid cells, and dysregulated communication between the three cell types drives ocular neovascular diseases (ONDs) that are currently treated with anti-VEGF agents that target endothelial cells only. In this proposal, we identify the secreted Slit2 ligand as an activator of retinal neovascularization that acts through Robo receptor signaling in pericytes and myeloid cells, and show that Slit-Robo pathway inhibition reduces OND in mouse models. By identifying mechanisms of Robo-mediated signaling in pericytes and myeloid cells we will uncover novel biology controlling retinal development and homeostasis that could be applied to OND prevention and may confer additional benefit over VEGF inhibition of endothelial cells alone.