Inhibition of VEGF receptor dimerization and signaling in corneal lymphangiogenes

摘要： 角膜淋巴管生成在严重的角膜损伤和感染后发生，是 导致失明的主要原因。在正常的生理条件下，角膜是 淋巴管位于结膜内，周围有淋巴管环绕。 角膜淋巴管生成特权得以维持。然而，受伤和感染 诱导角膜淋巴管生成。调节角膜的外在因素 淋巴管生成特权包括：1)存在血管生成和淋巴管生成 因子(VEGF-A、-C和-D)；2)sVEGFR-2在角膜中的表达；3)表达 角膜上皮中的VEGFR-3和角膜中的其他抗淋巴管生成因子。 角膜淋巴管生成状态受正反向平衡的控制 淋巴因素。 目前关于角膜淋巴管生成特免性的假说是由外源性的 角膜独有的因素。除了有据可查的外部因素外， 调节角膜淋巴管生成特异度，VEGFR-2的变化可能调节 淋巴细胞中VEGFR3的激活也调节角膜淋巴管的生成。 我们的初步数据显示在患病的人中有角膜淋巴管生成。 碱烧伤后角膜与VEGFR-3表达增强的关系 眼角膜。此外，含有内皮抑素的片段在体外与VEGFR-3结合，并具有 抑制碱性成纤维细胞生长因子诱导的角膜淋巴管生成比抑制血管生成效果更好。血管内皮生长因子- C诱导VEGFR-3二聚化和小剂量VEGF-C对血管内皮细胞生长的影响 促进淋巴细胞增殖。 我们的长期目标是确定调节角膜的机制 淋巴管生成。拟议中的实验旨在确定 血管内皮生长因子-2/-3调控血管内皮生长因子受体-3诱导的同源二聚 异二聚化及其选择性抑制VEGFR-3的研究 角膜淋巴管生成过程中的同源二聚体。

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.