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S. Dell, P.S. Muether, S. Ricke, N. Kociok, A.M. Joussen; Corneal Neovascularization After Treatment With PDGF–Receptor– and PI3–K–Inhibitors . Invest. Ophthalmol. Vis. Sci. 2005;46(13):457.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Corneal neovascularization remain up to now an unsolved therapeutic problem. We have previously demonstrated that one of the pro– and anti–angiogenetic factors involved, the platelet derived growth factor (PDGF) is directly linked to vessel formation and stabilization and thus, is a possible target for anti–angiogenetic therapy by inhibiting agents. We now aim to further elucidate the mechanisms by which PDGF exerts its effects on corneal angiogenesis. Methods: Corneal neovascularization was induced in C57 mice by removal of the limbal epithelium (scraping). When mature vessels became present after seven days, mice were treated with the PDGF–receptor–ß–inhibitor AG 1296, the PI3–K–inhibitors wortmannin or LY294002, respectively, using an intraperitoneally implanted mini–osmotic pump. At day 14 after scraping, corneas of treated and untreated (control) mice were dissected and immuno–stained with FITC–CD31 for endothelial cells and with Cy3–SMA (smooth muscle actin) for pericytes. VEGF (vascular endothelial growth factor), Ang1/2 (Angiopoietin 1/2) and PDGF levels of treated and untreated corneas were determined by RT–PCR. Results: Mice treated with PDGF inhibitor AG 1296 showed an inhibition of corneal neovascularization and a reduction of pericytes in the new formed vessels compared to untreated animals. VEGF, Ang1 and PDGF expression was reduced in the corneas of AG 1296– treated mice compared to respective controls. Treatment with the PI3–K inhibitors wortmannin and LY29002 had similar effects, inducing a decrease of corneal neovascularization and a reduction of VEGF, Ang1 and PDGF mRNA levels. Conclusions: Inhibition of the PDGF signal pathway results in loss of pericytes and decrease of vessels in the neovascularized cornea correlating with reduced expression of PDGF, Ang1 and VEGF. Administration of wortmannin or LY294002 has similar results proving that PI–3 kinase is involved in the regulation of VEGF, Ang1 and PDGF. Since PDGF is a known stimulus for PI–3 kinase activation, we can hypothesize that the observed decrease in VEGF, Ang1 and PDGF levels upon administration of the PDGF inhibitor is caused by the decreased activation of the PI–3 kinase signaling cascade.
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