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D. Yuen, L. Chen; Molecular Regulation of High-Risk Corneal Transplantation Beds by Combined Blockade of VEGFR-2 and VEGFR-3. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1555.
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Corneal lymphangiogenesis (LG; the development of new lymphatic vessels) and hemangiogenesis (HG; the development of new blood vessels) constitute the afferent and efferent arms of the immune reflex arc in transplantation immunity, respectively. Their enhancement accelerates transplant rejection in the high-risk setting where grafting is performed in the inflamed and highly vascularized beds. In this condition, the rejection rate can be as high as 90%. The purpose of this study is to investigate the specific roles of VEGFR-3 (vascular endothelial growth factor receptor-3) and VEGFR-2 in corneal LG vs. HG, and to examine whether a combined blockade of both pathways will maximize the treatment effect and reverse a high-risk host bed toward normal conditions.
Corneal inflammatory LG and HG was induced in BALB/c mice (6-8 weeks of age) (Taconic, Hudson, NY) by a standardized three-suture placement model. Blocking antibodies of VEGFR-3 and/or VEGFR-2 (provided by ImClone Systems, New York) were administrated systemically twice a week on Day 0 and thereafter for two weeks. Whole-mount corneas were sampled at Day 14 for immunofluorescent microscopic studies using both CD31 (a panendothelial cell marker) and LYVE-1 (a lymphatic marker) antibodies. Digital images were analyzed by NIH Image J software. Corneal HG was also evaluated by ophthalmic slit-lamp examinations.
VEGFR-3 blockade alone demonstrated a strong inhibition effect on LG and a mild effect on HG. However, VEGFR-2 blockade alone suppressed more HG than LG. The combined treatment maximized the blockade effects on both HG and LG.
These data indicate that VEGFR-2 and VEGFR-3 pathways interact synergistically in corneal LG and HG. Their combined blockade may provide a new therapeutic strategy to treat high-risk corneal transplant rejection.
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