Müller glia-derived pseudohypoxia drives intraretinal ischemic vasculopathy and neurovascular dysfunction

Ischemic retinopathies are characterized by retinal vascular instability, increased vascular permeability, and progressive neurovascular dysfunction. However, the cell-type-specific mechanisms initiating these changes remain insufficiently defined. Müller glia are central regulators of retinal metabolic homeostasis and a major source of vascular endothelial growth factor (VEGF), which positions them as potential upstream drivers of ischemia-associated vascular pathology. Here, we describe a conditional genetic mouse model in which pseudohypoxic signaling is selectively induced in Müller glia through tamoxifen-inducible deletion of von Hippel-Lindau (Vhl) using an Slc1a3-CreER driver. Müller glia-targeted Vhl deletion resulted in robust upregulation of retinal VEGF, intraretinal microvascular abnormalities, focal vascular leakage, corneal hemorrhaging, and microaneurysms. Functional assessment revealed transient inner retinal electroretinographic deficits without overt neuronal loss, consistent with early neurovascular dysfunction. Collectively, these findings demonstrate that glial hypoxia signaling via Vhl knockout is sufficient to induce retinal ischemic vasculopathy reflective of clinical phenotypes, providing a tractable platform for dissecting glial contributions to retinal vascular disease.