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Updated: Jun 17, 2026
Oxygen-Induced Retinopathy Model for Ischemic Retinal Diseases in Rodents
Published on: September 16, 2020
Pleiotropic effects of YC-1 selectively inhibit pathological retinal neovascularization and promote physiological
M DeNiro1, A Al-Halafi, F H Al-Mohanna
1Research Department, King Khaled Eye Specialist Hospital, Aruba Street, P.O. Box.7191, Riyadh 11462, Kingdom of Saudi Arabia. mdeniro@kkesh.med.sa
Abstract:
Vascular endothelial growth factor (VEGF) and inducible nitric-oxide synthase (iNOS) have been implicated in ischemia-induced retinal neovascularization. Retinal ischemia has been shown to induce VEGF and iNOS expression. It has been postulated that one of the crucial consequences of iNOS expression in the ischemic retina is the inhibition of angiogenesis. Furthermore, iNOS was shown to be overexpressed in Müller cells from patients with diabetic retinopathy. YC-1, a small molecule inhibitor of hypoxia-inducible factor (HIF)-1 alpha, has been shown to inhibit iNOS expression in various tissue models. Our aim was to assess the pleiotropic effects of YC-1 in an oxygen-induced retinopathy (OIR) mouse model and evaluate its therapeutic potential in HIF-1- and iNOS-mediated retinal pathologies. Dual-injections of YC-1 into the neovascular retinas decreased the total retinopathy score, inhibited vaso-obliteration and pathologic tuft formation, and concomitantly promoted physiological retinal revascularization, compared with dimethyl sulfoxide (DMSO)-treated group. Furthermore, YC-1-treated retinas exhibited a marked increase in immunoreactivities for CD31 and von Willebrand factor and displayed significant inhibition in HIF-1alpha protein expression. Furthermore, YC-1 down-regulated VEGF, erythropoietin, endothelin-1, matrix metalloproteinase-9, and iNOS message and protein levels. When hypoxic Müller and neuoroglial cells were treated with YC-1, iNOS mRNA and protein levels were reduced in a dose-dependent fashion. We demonstrate that YC-1 inhibits pathological retinal neovascularization by exhibiting antineovascular activities, which impaired ischemia-induced expression of HIF-1 and its downstream angiogenic molecules. Furthermore, YC-1 enhanced physiological revascularization of the retinal vascular plexuses via the inhibition of iNOS mRNA and protein expressions. The pleiotropic effects of YC-1 allude to its possible use as a promising therapeutic iNOS inhibitor candidate for the treatment of retinal neovascularization.
Insights
YC-1, a hypoxia-inducible factor (HIF)-1 inhibitor, reduces pathological retinal neovascularization by downregulating vascular endothelial growth factor (VEGF) and inducible nitric-oxide synthase (iNOS). This compound promotes physiological retinal revascularization, showing therapeutic potential for retinal diseases.
Area of Science:
- Ophthalmology
- Molecular Biology
- Pharmacology
Background:
- Retinal neovascularization is linked to vascular endothelial growth factor (VEGF) and inducible nitric-oxide synthase (iNOS).
- iNOS overexpression in Müller cells is observed in diabetic retinopathy, potentially inhibiting angiogenesis.
- Hypoxia-inducible factor (HIF)-1 alpha regulates iNOS expression.
Purpose of the Study:
- To evaluate the therapeutic potential of YC-1, a HIF-1 inhibitor, in oxygen-induced retinopathy (OIR).
- To investigate YC-1's effects on HIF-1 and iNOS pathways in retinal neovascularization.
Main Methods:
- YC-1 was administered via dual-injection in an OIR mouse model.
- Retinal tissues were analyzed for retinopathy scores, neovascularization markers (CD31, von Willebrand factor), and protein/mRNA expression (HIF-1alpha, iNOS, VEGF).
- Hypoxic Müller and neuroglial cells were treated with YC-1 to assess iNOS modulation.
Main Results:
- YC-1 treatment decreased retinopathy scores, inhibited pathologic neovascularization, and promoted physiological revascularization.
- YC-1 significantly reduced HIF-1alpha protein expression and downregulated VEGF, iNOS, and other angiogenic factors.
- YC-1 dose-dependently inhibited iNOS mRNA and protein levels in hypoxic Müller and neuroglial cells.
Conclusions:
- YC-1 exhibits antineovascular activities by inhibiting ischemia-induced HIF-1 and downstream angiogenic molecules.
- YC-1 promotes physiological retinal revascularization through iNOS inhibition.
- YC-1 is a promising therapeutic candidate for treating retinal neovascularization by targeting iNOS.
