Inhibition of Endothelial HIF-1α by IDF-11774 Attenuates Retinal Neovascularization and Vascular Leakage.

PURPOSE

In ischemic retinopathy (IR), hypoxia-inducible factor (HIF)-1α contributes to vision-threatening pathological retinal neovascularization (RNV). This study investigated the therapeutic efficacy and action mechanisms of the newly developed HIF-1α inhibitor IDF-11774 for IR in hypoxia-exposed human umbilical vein endothelial cells (HUVECs) and human retinal microvascular endothelial cells (HRMECs), as well as an oxygen-induced retinopathy (OIR) model mice.

METHODS

The effect of IDF-11774 on HIF-1α expression in HUVECs was assessed by quantitative real-time polymerase chain reaction (RT-qPCR), immunoblotting, and immunostaining, and effects on angiogenic potential were evaluated by cell proliferation, scratch wound, Transwell, and tube formation assays. Pathological RNV and vascular permeability were analyzed by immunostaining, hematoxylin and eosin staining, and dye leakage assays on postnatal day (P)17 following intravitreal injection of IDF-11774 (18.4 ng) or vehicle at P12. Target genes were identified by RNA sequencing and validated by western blot and immunostaining. Electroretinography, TUNEL staining, and immunofluorescence staining were conducted to evaluate the retinal toxicity of intravitreal IDF-11774.

RESULTS

In HUVECs, IDF-11774 inhibited hypoxia-induced HIF-1α expression through proteasomal degradation and concomitantly suppressed proliferation, migration, and tube formation. In OIR mice, IDF-11774 significantly reduced RNV, facilitated revascularization in the vascular obliterated zone, and alleviated vascular leakage. The key vascular regulatory signaling pathways ANGPT2/TIE2 and PlGF were modulated by IDF-11774 in hypoxic HUVECs and HRMECs, as well as in OIR mice. High-dose IDF-11774 had no significant effects on the electroretinogram or retinal histology.

CONCLUSIONS

Inhibiting HIF-1α with IDF-11774 exerts multiple therapeutic and pathway-regulatory effects and demonstrates a favorable retinal safety profile, highlighting IDF-11774 as a potentially therapeutic strategy for IR.