Misdirected vascular growth frequently occurs in the neovascular diseases in the retina. However, the mechanisms are still not fully understood. In the present study, we created capillary-free zones in the central and peripheral retinas in neonatal mice by pharmacological blockade of vascular endothelial growth factor (VEGF) signaling. Using this model, we investigated the process and mechanisms of revascularization in the central and peripheral avascular areas. After the completion of a 2-day treatment with the VEGF receptor tyrosine kinase inhibitor KRN633 on postnatal day (P) 4 and P5, revascularization started on P8 in the central avascular area where capillaries had been dropped out. The expression levels of VEGF were higher in the peripheral than in the central avascular area. However, the expansion of the vasculature in the peripheral avascular retina remained suppressed until revascularization had been completed in the central avascular area. Additionally, we found disorganized endothelial cell division, misdirected blood vessels with irregular diameters, and abnormal fibronectin networks at the border of the vascular front and the avascular retina. In the central avascular area, a slight amount of fibronectin as non-vascular component re-formed to provide a scaffold for revascularization. Mechanistic analysis revealed that higher levels of VEGF attenuated the migratory response of endothelial cells without decreasing the proliferative activity. These results suggest that the presence of concentration range of VEGF, which enhances both migration and proliferation of the endothelial cells, and the structurally normal fibronectin network contribute to determine the proper direction of angiogenesis.

中文翻译：

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新生小鼠视网膜血管内皮生长因子受体短期阻断后血运重建的过程

错误定向的血管生长经常发生在视网膜的新生血管疾病中。然而，其机制仍未完全了解。在本研究中，我们通过血管内皮生长因子 (VEGF) 信号传导的药理学阻断在新生小鼠的中央和周边视网膜中创建了无毛细血管区。使用该模型，我们研究了中枢和外周无血管区域血运重建的过程和机制。在产后第 4 天和第 5 天用 VEGF 受体酪氨酸激酶抑制剂 KRN633 完成为期 2 天的治疗后，在毛细血管已脱落的中央无血管区域的 P8 开始血运重建。VEGF在外周的表达水平高于中央无血管区域。然而，周边无血管视网膜中脉管系统的扩张一直受到抑制，直到中央无血管区域的血运重建完成。此外，我们发现内皮细胞分裂紊乱，血管直径不规则，血管前缘和无血管视网膜边界异常纤连蛋白网络。在中央无血管区域，少量纤连蛋白作为非血管成分重新形成，为血运重建提供支架。机制分析表明，较高水平的 VEGF 会减弱内皮细胞的迁移反应，而不会降低增殖活性。这些结果表明 VEGF 浓度范围的存在，可增强内皮细胞的迁移和增殖，