VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment
VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment
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DOI：
10.1172/jci200420465
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发表时间：
2004-04-01
影响因子：
15.9
通讯作者：
Streilein, JW
中科院分区：
文献类型：
--
作者：
Cursiefen, C;Chen, L;Streilein, JW
淋巴管生成是肿瘤转移和移植致敏的重要起始步骤，由VEGF-C和-D对VEGFR 3的作用介导。相反，VEGF-A结合VEGFR 1和VEGFR 2，是一种必需的血管生成因子。我们重新评估了VEGF-A在淋巴管生成中的潜在作用，使用一种新的模型，其中淋巴管生成和血管生成都在正常无血管角膜中诱导。VEGF Trap是一种结合并中和VEGF-A但不结合并中和VEGF-C或VEGF-D的基于受体的融合蛋白，给予VEGF Trap可完全抑制损伤后血管生成和LYVE-1（+）淋巴管的生长。此外，在VEGF-A（164/164）或VEGF-A（188/188）转基因小鼠（每种转基因小鼠仅表达三种主要VEGF-A同种型中的一种）中，淋巴管生成和血管生成均显著减少。由于VEGF-A对巨噬细胞具有趋化性，我们在此证明炎症角膜中的巨噬细胞释放淋巴管生成VEGF-C/VEGF-D，我们评估了巨噬细胞募集在VEGF-A介导的淋巴管生成中发挥作用的可能性。无论是全身耗竭所有骨髓来源的细胞（辐射）或局部耗竭的巨噬细胞在角膜（使用氯膦酸盐脂质体）损伤前显着抑制血管生成和淋巴管生成。我们的结论是，VEGF-A募集单核细胞/巨噬细胞在诱导炎症性新生血管形成中起着至关重要的作用，通过提供/放大病理性血管生成和淋巴管生成所必需的信号。
Lymphangiogenesis, an important initial step in tumor metastasis and transplant sensitization, is mediated by the action of VEGF-C and -D on VEGFR3. In contrast, VEGF-A binds VEGFR1 and VEGFR2 and is an essential hemangiogenic factor. We re-evaluated the potential role of VEGF-A in lymphangiogenesis using a novel model in which both lymphangiogenesis and hemangiogenesis are induced in the normally avascular cornea. Administration of VEGF Trap, a receptor-based fusion protein that binds and neutralizes VEGF-A but not VEGF-C or -D, completely inhibited both hemangiogenesis and the outgrowth of LYVE-1(+) lymphatic vessels following injury. Furthermore, both lymphangiogenesis and hemangiogenesis were significantly reduced in mice transgenic for VEGF-A(164/164) or VEGF-A(188/188) (each of which expresses only one of the three principle VEGF-A isoforms). Because VEGF-A is chemotactic for macrophages and we demonstrate here that macrophages in inflamed corneas release lymphangiogenic VEGF-C/VEGF-D, we evaluated the possibility that macrophage recruitment plays a role in VEGF-A-mediated lymphangiogenesis. Either systemic depletion of all bone marrow-derived cells (by irradiation) or local depletion of macrophages in the cornea (using clodronate liposomes) prior to injury significantly inhibited both hemangiogenesis and lymphangiogenesis. We conclude that VEGF-A recruitment of monocytes/macrophages plays a crucial role in inducing inflammatory neovascularization by supplying/amplifying signals essential for pathological hemangiogenesis and lymphangiogenesis.