Response of experimental retinal neovascularization to thiazolidinediones.
OBJECTIVE
To determine the effect of thiazolidinediones (TZDs) on experimental retinal neovascularization.


METHODS
The ability of the TZDs troglitazone and rosiglitazone maleate (1-20 micromol/L) to inhibit retinal endothelial cell (REC) proliferation, migration, tube formation, and signaling was determined in response to vascular endothelial growth factor (VEGF). In vivo studies were performed using the oxygen-induced ischemia model of retinal neovascularization. Neonatal mice were treated with intravitreous injection of 0.5 microL of troglitazone (100 micromol/L) or rosiglitazone maleate (100 micromol/L), or vehicle, and retinal neovascularization was assayed qualitatively and quantitatively by means of angiography and histological examination.


RESULTS
Expression of the TZD receptor, peroxisome proliferator-activated receptor gamma, was confirmed in RECs by means of Western immunoblotting. Rosiglitazone and troglitazone inhibited VEGF-induced migration (P< .05), proliferation (P< .05), and tube formation (P< .01) by RECs in vitro beginning at 10 micromol/L. Rosiglitazone and troglitazone inhibited phosphorylation of extracellular signal-regulated mitogen-activated protein kinase 1 in RECs. Intravitreous injection of rosiglitazone or troglitazone inhibited development of retinal neovascularization (P< .01) but did not significantly inhibit VEGF overexpression in the ganglion cell layer of the ischemic retina.


CONCLUSIONS
The TZDs inhibit experimental retinal neovascularization with an effect that is primarily downstream of VEGF expression.


CONCLUSIONS
The TZDs are widely prescribed and should be evaluated for their potential to inhibit the progression of diabetic retinopathy.
Murata
T
T
Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Hata
Y
Y
Ishibashi
T
T
Kim
S
S
Hsueh
W A
WA
Law
R E
RE
Hinton
D R
DR
D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects; D005451:Fluorescein Angiography; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D007267:Injections; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D023421:Models, Animal; D010766:Phosphorylation; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism; D015861:Retinal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012171:Retinal Vessels / Q000187:drug effects* / Q000473:pathology; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism; D000077288:Troglitazone; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D002839:Chromans; D016228:Endothelial Growth Factors; D007004:Hypoglycemic Agents; D008222:Lymphokines; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D000077154:Rosiglitazone; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D000077288:Troglitazone