Abstract
Purpose :
IDF-11774, a novel hypoxia-inducible factor 1α (HIF-1α) inhibitor, demonstrates antiangiogenic potential in tumors. However, its role in the development of pathological retinal neovascularization (RNV) remains unclear. This study aimed to comprehensively investigate the effects and underlying mechanisms of IDF-11774 on oxygen-induced RNV.
Methods :
The impact of IDF-11774 on pathological retinal neovascularization was evaluated in a C57BL/6J mouse model of oxygen-induced retinopathy (OIR) through vitreous cavity injection. Changes in retinal neovascularization, blood-retinal barrier integrity, inflammatory cell infiltration, and neurotoxicity were assessed using whole-mount and frozen-section immunofluorescence staining. Human umbilical vein endothelial cell (HUVEC) behavior under IDF-11774 treatment was analyzed through Cell Counting Kit-8 assay, cell scratch, transwell assay, and Matrigel assays, quantifying proliferation, migration, and tube formation. Molecular mechanisms of IDF-11774 were further elucidated through network pharmacological target screening, Western blot analysis, and immunofluorescence.
Results :
IDF-11774 significantly reduced the RNV area and the number of preretinal neovascular cell nuclei in mice, concurrently enhancing blood-retinal barrier function and mitigating inflammatory cell infiltration. Evaluation of retinal neuron markers, including RBPMS and calretinin labeling, revealed no evidence of retinal neurotoxicity at therapeutic doses of IDF-11774. In vitro, IDF-11774 consistently inhibited VEGF-stimulated proliferation, scratch healing, transwell migration, and tube formation ability of HUVECs. Furthermore, IDF-11774 treatment markedly suppressed the HIF-1α/VEGF pathway and VEGFR2 expression in the mouse retina of the oxygen-induced retinopathy (OIR) model and hypoxia-induced HUVECs.
Conclusions :
Our findings underscore the efficacy of the small molecule inhibitor IDF-11774 in suppressing RNV by targeting the HIF-1α/VEGF pathway and inhibiting VEGFR2 expression. These results substantiate the potential of IDF-11774 as an innovative and promising therapeutic agent for RNV-related diseases.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.