Cyclooxygenase-2 in human and experimental ischemic proliferative retinopathy.
BACKGROUND
Intravitreal neovascular diseases, as in ischemic retinopathies, are a major cause of blindness. Because inflammatory mechanisms influence vitreal neovascularization and cyclooxygenase (COX)-2 promotes tumor angiogenesis, we investigated the role of COX-2 in ischemic proliferative retinopathy.


RESULTS
We describe here that COX-2 is induced in retinal astrocytes in human diabetic retinopathy, in the murine and rat model of ischemic proliferative retinopathy in vivo, and in hypoxic astrocytes in vitro. Specific COX-2 but not COX-1 inhibitors prevented intravitreal neovascularization, whereas prostaglandin E2, mainly via its prostaglandin E receptor 3 (EP3), exacerbated neovascularization. COX-2 inhibition induced an upregulation of thrombospondin-1 and its CD36 receptor, consistent with the observed antiangiogenic effects of COX-2 inhibition; EP3 stimulation reversed effects of COX-2 inhibitors on thrombospondin-1 and CD36.


CONCLUSIONS
These findings point to an important role for COX-2 in ischemic proliferative retinopathy, as in diabetes.
Sennlaub
F
F
Department of Pediatrics, Centre de Recherche, Hôpital Sainte-Justine, 3175, chemin de la Côte-Sainte-Catherine, Montréal, Québec, Canada H3T 1C5. fsennlaub@justine.umontreal.ca
Valamanesh
F
F
Vazquez-Tello
A
A
El-Asrar
A M
AM
Checchin
D
D
Brault
S
S
Gobeil
F
F
Beauchamp
M H
MH
Mwaikambo
B
B
Courtois
Y
Y
Geboes
K
K
Varma
D R
DR
Lachapelle
P
P
Ong
H
H
Behar-Cohen
F
F
Chemtob
S
S
D000328:Adult; D000368:Aged; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018955:CD36 Antigens / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D003930:Diabetic Retinopathy / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007511:Ischemia / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000187:drug effects / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051116:Receptors, Scavenger; D012160:Retina / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology; D019700:Thrombospondin 1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors; D018630:Vitreoretinopathy, Proliferative / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology
D018955:CD36 Antigens; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; C545647:PTGER3 protein, human; C545650:PTGER4 protein, human; C545648:Ptger3 protein, mouse; C545649:Ptger3 protein, rat; C545651:Ptger4 protein, mouse; C545652:Ptger4 protein, rat; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051116:Receptors, Scavenger; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D040301:Vascular Endothelial Growth Factor Receptor-2; D015232:Dinoprostone