Peroxisome proliferator-activated receptor-gamma ligands inhibit choroidal neovascularization.
OBJECTIVE
To determine the antiangiogenic effects of peroxisome proliferator-activated receptor (PPAR)-gamma 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-gamma 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-gamma ligands, troglitazone (TRO) and rosiglitazone (RSG; 0.1-20 microM), 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-gamma1 was expressed in both RPE and CEC. PPAR-gamma 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-gamma ligands suggests the potential application of these agents in the large group of patients with age-related macular degeneration complicated by CNV.
Murata
T
T
Department of Ophthalmology, Doheny Eye Institute, Los Angeles, CA, USA.
He
S
S
Hangai
M
M
Ishibashi
T
T
Xi
X P
XP
Kim
S
S
Hsueh
W A
WA
Ryan
S J
SJ
Law
R E
RE
Hinton
D R
DR
D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002829:Choroid / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D020256:Choroidal Neovascularization / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002839:Chromans / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000633:toxicity; D004730:Endothelium, Vascular / Q000378:metabolism; D005451:Fluorescein Angiography; D006801:Humans; D007267:Injections; D017075:Laser Coagulation; D008024:Ligands; D008222:Lymphokines / Q000633:toxicity; D008252:Macaca fascicularis; D008297:Male; D010857:Pigment Epithelium of Eye / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*; D000077288:Troglitazone; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D002839:Chromans; D016228:Endothelial Growth Factors; D008024:Ligands; D008222:Lymphokines; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000077154:Rosiglitazone; D000077288:Troglitazone