Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Department of Organic Synthesis, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Exp Eye Res. 2018 Mar;168:115-127. doi: 10.1016/j.exer.2017.12.007. Epub 2018 Feb 2.
A short-term blockade of the vascular endothelial growth factor (VEGF)-mediated pathway in neonatal rats results in formation of severe retinopathy of prematurity (ROP)-like retinal blood vessels. The present study aimed to examine the role of retinal neurons in the formation of abnormal retinal blood vessels. Newborn rats were treated subcutaneously with the VEGF receptor tyrosine kinase inhibitor, KRN633 (10 mg/kg), or its vehicle (0.5% methylcellulose in water) on postnatal day (P) 7 and P8. To induce excitotoxic loss of retinal neurons, N-methyl-D-aspartic acid (NMDA) was injected into the vitreous chamber of the eye on P9. Changes in retinal morphology, blood vessels, and proliferative status of vascular cells were evaluated on P11 and P14. The number of cells in the ganglion cell layer and the thickness of the inner plexiform layer and inner nuclear layer were significantly decreased 2 days (P11) after NMDA treatment. The pattern and degree of NMDA-induced changes in retinal morphology were similar between vehicle-treated (control) and KRN633-treated (ROP) rats. In ROP rats, increases in the density of capillaries, the tortuosity index of arteries, and the proliferating vascular cells were observed on P14. The expansion of the endothelial cell network was prevented, and the capillary density and the number of proliferating cells were reduced in NMDA-treated retinas of both control and ROP rats. Following NMDA-induced neuronal cell loss, no ROP-like blood vessels were observed in the retinas. These results suggest that retinal neurons play an important role in the formation of normal and ROP-like retinal blood vessels.
新生大鼠血管内皮生长因子（VEGF）介导途径的短期阻断会导致严重的早产儿视网膜病变（ROP）样视网膜血管形成。本研究旨在探讨视网膜神经元在异常视网膜血管形成中的作用。新生大鼠于生后第 7 天和第 8 天皮下给予 VEGF 受体酪氨酸激酶抑制剂 KRN633（10mg/kg）或其载体（0.5%甲基纤维素水溶液）。于第 9 天向玻璃体腔内注射 N-甲基-D-天冬氨酸（NMDA）诱导视网膜神经元兴奋性毒性丧失。于第 11 天和第 14 天评估视网膜形态、血管和血管细胞增殖状态的变化。NMDA 处理后 2 天（第 11 天），节细胞层中的细胞数量和内丛状层和内核层的厚度显著减少。NMDA 诱导的视网膜形态变化的模式和程度在载体处理（对照）和 KRN633 处理（ROP）大鼠之间相似。在 ROP 大鼠中，第 14 天观察到毛细血管密度、动脉迂曲指数和增殖性血管细胞增加。内皮细胞网络的扩张被阻止，并且在对照和 ROP 大鼠的 NMDA 处理视网膜中，毛细血管密度和增殖细胞数量减少。在 NMDA 诱导的神经元细胞丧失后，在视网膜中未观察到 ROP 样血管。这些结果表明，视网膜神经元在正常和 ROP 样视网膜血管形成中起重要作用。
