Inhibition of VEGF receptor dimerization and signaling in corneal lymphangiogenes

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ABSTRACT: Corneal lymphangiogenesis follows severe corneal injuries and infections and is one of the major causes of blindness. Under normal physiological conditions, the cornea is alymphatic and surrounded by lymphatic vessels residing in the conjunctiva while corneal lymphangiogenic privilege is maintained. However, wounding and infection induce corneal lymphangiogenesis. The extrinsic factors that regulate corneal lymphangiogenic privilege include: 1) the presence of angiogenic and lymphangiogenic factors (VEGF-A, -C and -D); 2) expression of sVEGFR-2 in the cornea; 3) expression of VEGFR-3 in corneal epithelium and other anti-lymphangiogenic factors in the cornea. The status of corneal lymphangiogenesis is controlled by the balance of pro- and anti- lymphatic factors. The current hypothesis of corneal lymphangiogenic privilege is governed by extrinsic factors unique to the cornea. Besides the well-documented extrinsic factors involved in regulating corneal lymphangiogenic privilege, changes in the VEGFR-2 may regulate VEGFR3-activation in lymphatic cells also regulate corneal lymphangiogenesis. Our preliminary data demonstrated corneal lymphangiogenesis in diseased human corneas, which correlated with enhanced VEGFR-3 expression in alkali-burn-wounded corneas. In addition, endostatin-containing fragments bind to VEGFR-3 in vitro and have better inhibition of bFGF-induced corneal lymphangiogenesis than angiogenesis. VEGF- C-induced VEGFR-3 dimerization and low dose VEGF-C has better potency in promoting lymphatic cell proliferation. Our long-term objective is to identify the mechanisms that regulate corneal lymphangiogenesis. The proposed experiments are designed to determine the role of VEGF-C-induced VEGFR-3 homodimerization regulated by VEGF-2/-3 heterodimerization and to investigate selective inhibitors for the inhibition of VEGFR-3 homodimerization during corneal lymphangiogenesis.