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A. G. Scicli, A. M. Guo, G. M. Scicli, P. Chen, P. A. Edwards, P. A. Edwards; Inhibition of Arachidonic Acid -Hydroxylases of the Cyp 4A/F Family Suppress Angiogenic and Pro-Inflammatory Responses to VEGF and Diabetes-Induced Retinal Leukostasis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):49.
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To determine if inhibition of 20-HETE synthesis alters the angiogenic and retinal leukostasis effects of VEGF.
To study whether 20-HETE is involved in angiogenic responses to VEGF, we used the rat cornea pocket angiogenesis assay, and the highly selective inhibitor of CYP4A and 20-HETE synthesis, N-hydroxy-N’-(4-butyl-2-methylphenol) formamidine (HET0016). Hydron pellets containing 250 ng of VEGF either alone or together with 20 µg HET0016 were implanted into the stroma of the cornea adjacent to the temporal limbus. Vessel length (pixels) and area covered by vessels (pixels2) were measured using image analysis software. To study the role of 20-HETE in VEGF and diabetes-induced retinal leukostasis, VEGF (50 ng) alone or together with HET0016 (20 µg) was injected ivt. Rats with streptozotocin-induced diabetes were treated with HET0016 (10 mg/kg/day) for 14 days. Retinal leukostasis was determined using the acridine-orange- Scanning Laser Ophthalmoscope technique, and expressed as leukocytes/mm2.
There was negligible neovascularization in untreated eyes: vessel length in saline -treated controls was 580 ± 100. VEGF markedly increased vessels length to 17, 600±2900; vessels were almost absent in the corneas of rats treated with both VEGF and HET0016: vessel length was 1,200 ± 300. Ivt VEGF increased retinal leukostasis by ~ 18 fold, from 0.07 to 1.3 leukocyte/mm2. Co-treatment with HET0016 reduced the VEGF-induced leukostasis to 0.5 leukocyte/mm2 (p < 001 vs VEGF). Retinal leukostasis in diabetes was increased 17 fold compared with controls to 1.3 leukocytes/mm2, and this was markedly decreased by HET0016 to 0.25 leukocytes/mm2 (p <0.01 vs. diabetes).
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