Microglial HMOX1 drives retinal angiogenesis via modulation of endothelial STAT3 signaling.

Abstract

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness and is characterized by retinal neovascularization. Microglia have emerged as key mediators of hypoxia-induced angiogenesis, yet the underlying molecular mechanisms remain incompletely defined. Heme oxygenase-1 (HMOX1) is a stress-inducible enzyme with well-established antioxidant and anti-inflammatory properties, acting as an important electrophilic signaling mediator in redox biology. Here, we investigated the role of microglial HMOX1 in retinal angiogenesis and its regulation of endothelial signaling. Using an oxygen-induced retinopathy (OIR) mouse model combined with bulk and single-cell RNA sequencing, we identified HMOX1 as a hypoxia-induced angiogenic regulator selectively enriched in retinal microglia. Conditional knockout of HMOX1 in microglia markedly reduced neovascularization in vivo, while in vitro hypoxia-driven microglia-endothelial co-culture assays confirmed impaired endothelial proliferation, migration, and tube formation. Mechanistically, loss or pharmacological inhibition of HMOX1 suppressed STAT3 activation and VEGF expression in endothelial cells, establishing a paracrine signaling pathway between microglia and endothelium. These findings demonstrate that microglial HMOX1 drives pathological angiogenesis by activating the endothelial STAT3-VEGF axis. Our study uncovers a novel hypoxia-microglia-endothelium signaling mechanism, highlighting microglial HMOX1 as a promising therapeutic target for ROP and other hypoxia-related angiogenic diseases.