VEGF is an angiogenic and permeability-enhancing factor that is linked to retinal ischemia-associated neovascularization. In the human, increased vitreous VEGF correlated with retinal ischemia-related neovascularization in diabetic retinopathy, retinal vein occlusion, and ROP.
44 VEGF
121 (VEGF
120 in rats) appears to be the dominant isoform induced by IGF-I and is a major retinal isoform.
45 This isoform is bioactive, freely soluble, and a major mediator of angiogenesis. All the murine VEGF isoforms were present in our rat retinas with equivalent abundance. Whereas VEGF
188 remained unaffected by ibuprofen and indomethacin, VEGF
164 was downregulated with the high dose of ibuprofen and both doses of indomethacin. However, only ibuprofen suppressed VEGF
120 mRNA expression. Because VEGF
120 is the dominant isoform induced by IGF-I, this finding suggests that the high dose of ibuprofen suppresses VEGF
120 through decreased uptake of retinal IGF-I and provides further evidence that ibuprofen is more effective than indomethacin for suppression of retinal VEGF. The cellular effects of VEGF are mediated by VEGFR-1 and -2, which are expressed exclusively by endothelial cells. Knockout studies in mice have shown that the VEGFR-1 receptor mediates organization of the vasculature,
46 whereas VEGFR-2 mediates endothelial cell differentiation and proliferation.
47 Our data showed that ibuprofen suppressed VEGFR-2, suggesting decreased VEGF signaling and retinal vascular growth. It should be noted that this inhibition was observed only at higher concentrations, which are needed to inhibit prostaglandin synthesis. Despite the ability of both ibuprofen and indomethacin to inhibit COX, the differences between the two drugs were remarkable. These differences may be due to their selectivity for COX-1 and COX-2. Using murine COX-null cell systems, Kirtikara et al.
48 demonstrated that ibuprofen was more selective for COX-2 than indomethacin based on COX-2 IC
50/COX-1 IC
50 ratio ranking. A similar finding was reported by Uzan.
49 The interaction between COX-2 and VEGF is well-documented. Treatment with VEGF increased COX-2 but not COX-1 protein in a dose-dependent manner in endothelial cells.
50 51 Therefore, in our study, it seems plausible to speculate that ibuprofen at high doses may exert its effect on VEGF through COX-2. However, further studies are needed to confirm or refute this speculation.