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D. Scott McLeod, Makoto Taomoto, Jingtai Cao, Zhenping Zhu, Larry Witte, Gerard A. Lutty; Localization of VEGF Receptor-2 (KDR/Flk-1) and Effects of Blocking It in Oxygen-Induced Retinopathy. Invest. Ophthalmol. Vis. Sci. 2002;43(2):474-482.
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purpose. Vascular endothelial cell growth factor (VEGF) has been implicated in
vascular development and in proliferative retinopathies. The goal of
this study was to examine the immunohistochemical localization and
relative levels of VEGF receptor-2 (KDR) in canine retina during
postnatal vasculogenesis and during angiogenesis in oxygen-induced
retinopathy (OIR) and to investigate the effects of neutralizing KDR on
methods. Eyes from normal dogs ranging from 1 to 22 days of age and age-matched
oxygen-treated animals were snap frozen for immunohistochemical
analysis with antibodies against human KDR. To examine the effects of
blocking KDR, 6-day-old air-reared control and oxygen-treated animals
were surgically implanted with slow release polymer pellets
containing control IgG or anti-KDR. Material eluted from pellets was
assessed using a binding assay (measures binding to soluble KDR) to
determine the kinetics of anti-KDR release and endothelial cell
proliferation to measure bioactivity. Animals were killed at 22 days
of age and tissues examined with adenosine diphosphatase (ADPase)
histochemical staining of blood vessels.
results. KDR immunoreactivity was only weakly associated with developing retinal
vessels and was not observed in angioblasts throughout normal postnatal
development. Immunoreactivity was very strong in reforming retinal
vessels and intravitreal neovascularization in oxygen-treated animals.
Anti-KDR had no effect on vessel morphology or growth in air-reared
control animals. In oxygen-treated animals, anti-KDR significantly
inhibited revascularization of the retina (P =
0.005) and formation of intravitreal neovascularization compared with
control IgG pellet eyes (P < 0.04).
conclusions. KDR/Flk-1 was only weakly associated with normal developing primary
retinal vessels but was strongly expressed by proliferating endothelial
cells in reforming retinal vessels and intravitreal neovascularization
after hyperoxic insult. Anti-KDR antibody delivered by slow-release
pellets had no effect on normal vasculogenesis, but it inhibited the
formation of intravitreal neovascularization and retinal vessel
development in OIR. The study suggests that blocking KDR may be
beneficial for treating pathologic angiogenesis in adult
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