COX-2 inhibition and retinal angiogenesis in a mouse model of retinopathy of prematurity.
OBJECTIVE
The prostaglandin-cyclooxygenase (COX) pathway influences new blood vessel growth in a variety of tissues. This study was conducted to determine the cellular location of COX-2 in the retina and whether the inhibition of COX-2 would reduce retinal angiogenesis in a rodent model of retinopathy of prematurity (ROP).


METHODS
ROP was induced in C57BL/6 mice by exposing 7-day-old mice to 75% oxygen (hyperoxia) for 5 days followed by 5 days in room air (relative hypoxia and retinal angiogenesis). Normal mice were those with a normally developing retinal vasculature exposed to room air from birth until postnatal day (P)17. The COX-2 inhibitor, rofecoxib (15 mg/kg body weight intraperitoneally) was administered to normal and ROP mice from P12 to P17. Immunohistochemistry for COX-2 was performed on retinas from all groups by the avidin-biotin method. Histologic methods were used to count blood vessel profiles (BVPs) in the inner retina (inner limiting membrane, ganglion cell layer, and inner plexiform layer) with a masked approach.


RESULTS
Intense COX-2 immunolabeling was specifically localized to ganglion cells and blood vessels of all mice retinas. In ROP mice, COX-2 immunolabeling was detected on blood vessels extending into the vitreous cavity. Quantitation of BVPs in the inner retina revealed an increase in untreated ROP mice compared with untreated normal mice (P < 0.001). Rofecoxib decreased BVPs by approximately 45% in normal mice and 37% in ROP mice.


CONCLUSIONS
COX-2 is localized to sites associated with retinal blood vessels. The finding that the selective COX-2 inhibitor, rofecoxib, attenuated the retinal angiogenesis that accompanies ROP, and normal retinal development indicates that COX-2 plays an important role in blood vessel formation in the retina.
Wilkinson-Berka
Jennifer L
JL
Department of Physiology, University of Melbourne, Parkville, Victoria, Australia. j.berka@physiology.unimelb.edu.au
Alousis
Nicole S
NS
Kelly
Darren J
DJ
Gilbert
Richard E
RE
D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018496:Hyperoxia; D007124:Immunoenzyme Techniques; D007231:Infant, Newborn; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000201:enzymology; D015861:Retinal Neovascularization / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D012171:Retinal Vessels / Q000201:enzymology; D012178:Retinopathy of Prematurity / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D013450:Sulfones
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D013450:Sulfones; C116926:rofecoxib; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases