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C. Cursiefen, L. Chen, D. Jackson, J. Rudge, S. Wiegand, R. Dana, W. Streilein; Complete Inhibition of Simultaneous Onset Corneal Lymphangiogenesis and Angiogenesis by Trapping Vascular Endothelial Growth Factor (VEGF) Using a VEGF Receptor 1 and 2 Chimeric Protein (VEGF TrapR1R2) . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3214.
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Purpose: Neovascularization of the cornea creates a high-risk bed for penetrating keratoplasty. We sought to determine if lymphangiogenesis accompanies hemangiogenesis in a murine model of corneal neovascularization, and if so, whether lymphangiogenesis can be inhibited by a molecular "trap" designed to neutralize endogenous VEGF. Methods: Intrastromal sutures were placed in eyes of BALB/c mice treated intraperitoneally with 12.5 mg/kg VEGF TrapR1R2 (a chimeric protein consisting of VEGF receptor 1 and 2 domains coupled to a Fc-fragment) or with human Fc-protein alone (control). Corneal blood and lymph angiogenesis were quantified by slit-lamp examination, and by immunofluorescence microscopy and morphometry using CD31 as a panendothelial and LYVE-1 as a lymphatic endothelial-specific marker. Results: In mice treated with control Fc-protein, CD31+/LYVE-1+ lymphatic vessels were consistently observed to accompany new CD31+/LYVE-1- corneal blood vessels, starting within 1 day, and being easily detectable biomicroscopically at day 3. Neutrophils were conspicuous during early angiogenesis. A single treatment with VEGF TrapR1R2 virtually prevented both blood and lymph angiogenesis during the first week post-suture. Conclusions: Lymphangiogenesis is an early concomitant of hemangiogenesis in this murine model, and growth factors of the VEGF family are essential since their neutralization by an agent comprising the ligand binding domains of VEGF receptor 1 and 2 inhibited both responses. Early induction of lymphangiogenesis in the suture-induced model of corneal neovascularization offers an explanation for why recipient sensitization to donor cornea allograft antigens is so rapid, and why prompt, universal graft rejection occurs. Selective block of hem- and lymphangiogenesis might promote survival of cornea allografts in high-risk beds.
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