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Blockade of vascular endothelial cell growth factor receptor signaling is sufficient to completely prevent retinal
1Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Abstract:
Retinal vasculogenesis and ischemic retinopathies provide good model systems for study of vascular development and neovascularization (NV), respectively. Vascular endothelial cell growth factor (VEGF) has been implicated in the pathogenesis of retinal vasculogenesis and in the development of retinal NV in ischemic retinopathies. However, insulin-like growth factor-I and possibly other growth factors also participate in the development of retinal NV and intraocular injections of VEGF antagonists only partially inhibit retinal NV. One possible conclusion from these studies is that it is necessary to block other growth factors in addition to VEGF to achieve complete inhibition of retinal NV. We recently demonstrated that a partially selective kinase inhibitor, PKC412, that blocks phosphorylation by VEGF and platelet-derived growth factor (PDGF) receptors and several isoforms of protein kinase C (PKC), completely inhibits retinal NV. In this study, we have used three additional selective kinase inhibitors with different selectivity profiles to explore the signaling pathways involved in retinal NV. PTK787, a drug that blocks phosphorylation by VEGF and PDGF receptors, but not PKC, completely inhibited retinal NV in murine oxygen-induced ischemic retinopathy and partially inhibited retinal vascularization during development. CGP 57148 and CGP 53716, two drugs that block phosphorylation by PDGF receptors, but not VEGF receptors, had no significant effect on retinal NV. These data and our previously published study suggest that regardless of contributions by other growth factors, VEGF signaling plays a critical role in the pathogenesis of retinal NV. Inhibition of VEGF receptor kinase activity completely blocks retinal NV and is an excellent target for treatment of proliferative diabetic retinopathy and other ischemic retinopathies.
Insights
Vascular endothelial growth factor (VEGF) is critical for retinal neovascularization (NV). Blocking VEGF receptor kinase activity completely inhibits retinal NV, offering a promising treatment for ischemic retinopathies.
Area of Science:
- Ophthalmology
- Vascular Biology
- Pharmacology
Background:
- Retinal vasculogenesis and ischemic retinopathies are models for vascular development and neovascularization (NV).
- Vascular endothelial growth factor (VEGF) is implicated in retinal NV, but other growth factors may also contribute.
- Previous studies showed partial inhibition of retinal NV with VEGF antagonists, suggesting the need to block multiple pathways.
Purpose of the Study:
- To explore signaling pathways involved in retinal NV using selective kinase inhibitors.
- To determine the critical role of VEGF signaling in retinal NV pathogenesis.
- To evaluate potential therapeutic targets for ischemic retinopathies.
Main Methods:
- Utilized murine oxygen-induced ischemic retinopathy model.
- Administered selective kinase inhibitors targeting VEGF and/or PDGF receptors.
- Assessed the effect of inhibitors on retinal NV and vascularization.
Main Results:
- PTK787, a VEGF/PDGF receptor inhibitor, completely inhibited retinal NV.
- CGP 57148 and CGP 53716, PDGF receptor inhibitors, had no significant effect on retinal NV.
- VEGF receptor kinase inhibition effectively blocked retinal NV.
Conclusions:
- VEGF signaling plays a critical role in the pathogenesis of retinal NV.
- Complete inhibition of retinal NV is achievable by blocking VEGF receptor kinase activity.
- VEGF receptor kinase inhibition is a potential therapeutic strategy for proliferative diabetic retinopathy and other ischemic retinopathies.