Endothelial Yes-Associated Protein 1 Promotes Astrocyte Proliferation and Maturation via Cytoplasmic Leukemia Inhibitory Factor Secretion in Oxygen-Induced Retinopathy

PURPOSE: Purpose The role of endothelial Yes-associated protein 1 (YAP) in the pathogenesis of retinal angiogenesis and the astrocyte network in the mouse oxygen-induced retinopathy (OIR) model is unknown. METHODS: For in vivo studies, OIR was induced in conditional endothelial YAP knockout mice and their wild-type littermates. Retinal vascularization and the astrocyte network were evaluated by whole-mount fluorescence and Western blotting. In vitro experiments were performed in astrocytes cultured with human microvascular endothelial cell-1–conditioned medium to analyze the mechanisms underlying the effect of endothelial YAP on astrocytes. RESULTS: Endothelial YAP deletion not only impaired retinal blood vessels, but also caused a sparse and disrupted astrocyte network in response to OIR. Levels of the immature astrocyte marker (platelet-derived growth factor A) in the retina were substantially increased owing to YAP deficiency, suggesting a possible failure in astrocyte maturation, whereas retinal expression of leukemia inhibitory factor (LIF) was decreased. In vitro studies suggested that loss or overexpression of YAP resulted in elevated or decreased LIF secretion by human microvascular endothelial cell-1, respectively. Increased LIF levels in the culture medium promoted astrocyte maturation and proliferation and rescued YAP inhibition-induced astrocyte loss. Finally, activating YAP could protect against the pathology of the astrocyte network and even suppress pathologic retinal vascularization in control OIR mice, but not in endothelial YAP-deficient OIR mice. CONCLUSIONS: Endothelial YAP regulation of LIF secretion is required for normalized astrocyte network formation in OIR, thereby providing a novel target for protecting the astrocyte network and thus benefiting retinal blood vessels.