Zeb2 Controls Retinal Physiological and Pathological Angiogenesis by Regulating Astrocyte Proliferation and Differentiation

ABSTRACT Retinal angiogenesis relies on a precisely timed interaction between astrocytes and endothelial cells (ECs), yet the transcriptional regulatory program underlying this complex neurovascular crosstalk remains poorly characterized. Here, we define Zeb2 as a pivotal transcriptional modulator of retinal astrocyte function that coordinates developmental and pathological vascular growth. It is transiently expressed in retinal astrocyte progenitor cells during development and re‐induced under pathological hypoxia. Conditional ablation of Zeb2 in retinal astrocytes enhanced their proliferation, migration, and maturation by upregulating VEGFA and altering other signalling, leading to excessive superficial vascular growth during development. In oxygen‐induced retinopathy, Zeb2 inactivation exacerbated pathological neovascularization while impairing reparative revascularization, which is associated with a transcriptional signature favouring tuft ECs over tip ECs. Mechanistically, it inhibited the neurotoxic A1 astrocyte identity, resulting in dampened inflammatory response and diminished genetic program promoting revascularization and/or preventing neovascularization including Plxnd1, Nrf2, and FGF2 signalling. These findings establish Zeb2 as an oxygen‐sensitive regulator of astrocyte function that differentially modulates physiological and pathological angiogenesis, highlighting its potential as a therapeutic target in proliferative retinopathies.