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.