Abstract
Abstract: :
Purpose: Cyclooxygenas 2 (Cox-2) is induced in many hypoxic conditions. Prostaglandine E2 (PGE2), produce of Cox-2 activity, has been shown to promote angiogenesis in many models. To investigate the role of Cox-2 in retinal neovascularization, we studied the expression of Cox-2 and the effect of a specific Cox-2 inhibitor in the mouse ischemic proliferative retinopathy model. Methods: Mice were exposed from post-natal day 7 (P7) to P12 to 75±2% oxygen, leading to vessel rarefaction and the development of a central avascular area. From P12 to P17 mice were raised in room air, resulting in relative hypoxia. Cox-2 mRNA expression was determined by RT-PCR. Cox2 protein was evaluated by western blot analysis and immunohistochemistry. The influence of Cox-2 on normal vascular development and in ischemic proliferative retinopathy was evaluated by comparing intraretinal and intravitreal endothelial cell proliferation in mice treated with two intravitreal injections (P13 and P15 (n=6+ per group)) of either a specific Cox-2 inhibitor (APHS 0,6 / 3 / 15 mg/ml) or PGE-2. (0,5 / 5 mg/ml). Results: RT PCR (at P12, P14 and P17) and Western blot analysis (at P14) demonstrated the expression and the translation of Cox-2 messenger in room air raised and in oxygen incubated animals. Immunohistochemistry at P14 revealed Cox-2 in the ROP layer and in the inner plexiform layer of normoxic and hypoxic retinas.. Inhibition of Cox-2 by APHS had no effect on the retinal vasculature of room air raised mice. The inhibition of Cox-2 by APHS injection in the hypoxic phase of the model, resulted in a dose dependent inhibition of intravitreal neovascularization (up to 50%). No effect was observed on intraretinal revascularization. On the other hand, the injectionof PGE2 exacerbated pre-retinal neovascularization. Conclusion: Cox-2 is expressed in normal retinal development between P12 and P17, as well as under hyperoxic and hypoxic conditions in the murine retina. However Cox-2 activity, or PGE2 endothelial cell sensitivity, seems to be upregulated under hypoxic conditions, as specific inhibition of Cox-2 inhibited intravitreal neovascularization in a dose dependent manner. Intraretinal revascularization was not altered by Cox-2 inhibition. Cox-2 inhibitors could have potential therapeutic interest in pre retinal neovascularization in ischemic prliferative retinopathy.
Keywords: 566 retinal neovascularization • 316 animal model • 476 molecular biology