Molecular hydrogen promotes retinal vascular regeneration and attenuates neovascularization and neuroglial dysfunction in oxygen-induced retinopathy mice.

Abstract

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness, and current interventions carry notable complication risks. This study examined the effects of 3–4% hydrogen gas inhalation in oxygen-induced retinopathy (OIR) mice (wild-type and Nrf2-knockout), assessing vascular obliteration, pathological neovascularization, and neuroglial changes. Hydrogen inhalation did not impair physiological angiogenesis but reduced vaso-obliteration and abnormal vessel growth. Retinal astrocyte density and morphology were preserved, and microglial activation—particularly in neovascular zones—was diminished. Mechanistically, hydrogen promoted Nrf2 activation, suppressed Dll4-driven Notch signaling, and modulated HIF-1α/VEGF pathways. In vitro experiments using HUVECs under hypoxia corroborated these findings, showing enhanced proliferation alongside reduced ROS levels via Nrf2 and Dll4/Notch pathway regulation. These results suggest that molecular hydrogen exerts protective effects on retinal vasculature and glia in OIR through coordinated Nrf2-Notch and HIF-1α/VEGF signaling.

Mechanism

Hydrogen activates Nrf2 to reduce reactive oxygen species and suppresses Dll4-induced Notch signaling to inhibit pathological neovascularization, while modulating HIF-1α/VEGF pathways to support physiological retinal revascularization.