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Ligands Inhibit Choroidal Neovascularization
From the Departments of 1 Ophthalmology and 2 Pathology, Keck School of Medicine of the University of Southern California and 3 Doheny Eye Institute, Los Angeles; Department of 4 Ophthalmology, Kyushu University, Fukuoka, Japan; 5 Division of Endocrinology, Diabetes and Hypertension, University of California, Los Angeles, School of Medicine.
PURPOSE. To determine the antiangiogenic effects of peroxisome
proliferator–activated receptor (PPAR)-
agonists on ocular cells
involved in the pathogenesis of choroidal neovascularization (CNV) in
vitro and on experimental laser photocoagulation–induced CNV in vivo.
METHODS. PPAR- expression in human retinal pigment epithelial (RPE) cells and
bovine choroidal endothelial cells (CECs) was determined using an RNase
protection assay and Western blot analysis. Two PPAR- ligands,
troglitazone (TRO) and rosiglitazone (RSG; 0.1–20 µM), were used to
assess effects on RPE and CEC proliferation and migration and CEC tube
formation in response to vascular endothelial growth factor (VEGF). The
effects of intravitreal injection of TRO on laser
photocoagulation–induced CNV lesions in rat eyes (15 experimental, 15
control, nine burns per eye) and cynomolgus monkey eyes (two
experimental, two control, seven paramacular burns per eye) was
assessed by fluorescein angiography and histologic evaluation.
RESULTS. PPAR-1 was expressed in both RPE and CEC. PPAR- ligands
significantly inhibited VEGF-induced migration and proliferation in
both cell types and tube formation of CEC in a dose–response manner.
CNV in rats was markedly inhibited by intravitreous injection of TRO
(P < 0.001). Lesions showed significantly less
fluorescein leakage and were histologically thinner in the TRO-treated
animals. Similar findings were present in the TRO-treated lesions in
two monkey eyes. The drug showed no apparent adverse effects in the
adjacent retina or in control eyes.
CONCLUSIONS. The inhibition of VEGF-induced choroidal angiogenesis in vitro, and CNV
in vivo by PPAR- ligands suggests the potential application of these
agents in the large group of patients with age-related macular
degeneration complicated by CNV.
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