Intravitreal sustained release of VEGF causes retinal neovascularization in rabbits and breakdown of the blood-retinal barrier in rabbits and primates
Intravitreal sustained release of VEGF causes retinal neovascularization in rabbits and breakdown of the blood-retinal barrier in rabbits and primates
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DOI：
10.1006/exer.1996.0239
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发表时间：
1997-04-01
影响因子：
3.4
通讯作者：
Oshima, K
中科院分区：
文献类型：
--
作者：
Ozaki, H;Hayashi, H;Oshima, K
血管内皮生长因子(VEGF)已被认为是视网膜新生血管(NV)的一种可能的介质，但尚不确定单独使用血管内皮生长因子是否足以引起视网膜NV。我们试图通过植入乙烯-乙酸乙烯酯共聚物小球来研究这个问题，这种小球可以缓慢地将血管内皮生长因子释放到兔和灵长类动物的玻璃体腔中。采用间接检眼镜、眼底照相和荧光素眼底血管造影术，在不同时间点处死动物，进行免疫细胞化学和超微结构检查。兔玻璃体腔内植入含30mg人重组VEGP的微球后7d，视网膜血管扩张、弯曲，第14~21d，所有眼均可见视网膜新生血管。荧光素血管造影显示大量染料从异常血管中渗出。增殖细胞核抗原免疫组织化学染色显示视网膜表面新生血管内皮细胞胞核呈阳性染色。6只眼植入含有载药剂的对照微球，2只眼植入单独含有30微克人血清白蛋白的微球，未见视网膜血管异常。将含有100微克血管内皮生长因子的微球植入灵长类动物的玻璃体腔内，导致虹膜新生血管和视网膜血管扩张和弯曲，与人类缺血性视网膜病变非常相似。血清白蛋白免疫组织化学染色显示血视网膜屏障(BRB)广泛严重破坏。组织学可见扩张的薄壁视网膜血管，但不能明确识别视网膜NV，且增殖细胞核抗原染色阴性。这些结果表明，持续的玻璃体内释放的血管内皮生长因子导致广泛的视网膜血管扩张和BRB的破裂。视网膜NV似乎需要视网膜表面持续高水平的血管内皮生长因子，可以在兔身上实现，提供了一种潜在的有用的视网膜NV模型，但在灵长类动物中很难实现。血管内皮生长因子诱导的血-视网膜屏障的广泛破坏表明，血管内皮生长因子拮抗剂可能为缺血性视网膜病变和黄斑水肿患者提供一种新的治疗方法。(C)1997年学术出版社有限公司。
Vascular endothelial growth factor (VEGF) has been identified as a possible mediator of retinal neooascularization (NV), but it is not certain if VEGF alone is sufficient to cause retinal NV. We sought to investigate this issue by implanting ethylene-vinyl acetate copolymer pellets that slowly release VEGF into the vitreous cavity of rabbits and primates. Eyes were examined by indirect ophthalmoscopy, fundus photography, and fluorescein angiography and then animals were killed at various time points and immunocytochemical and ultrastructural evaluations were carried out.Seven days after implantation of a pellet containing 30 mu g of human recombinant VEGP into the vitreous cavity of rabbits, retinal blood vessels became dilated and tortuous, and between days 14 and 21, retinal NV was noted in all eyes. Fluorescein angiography showed profuse leakage of dye from the anomalous vessels. Immunohistochemical staining for proliferating cell nuclear antigen (PCNA) showed positively staining nuclei in many of the endothelial cells of new blood vessels on the surface of the retina. Six eyes implanted with control pellets containing vehicle and two eyes implanted with pellets containing 30 mu g of human serum albumin alone showed no retinal Vascular abnormalities.Implantation of pellets containing 100 mu g of VEGF into the vitreous cavity of primates resulted in iris NV and retinal vascular dilation and tortuosity very much like that seen in humans with ischemic retinopathies. Immunohistochemical staining for serum albumin showed widespread severe breakdown of the blood-retinal barrier (BRB). Histology showed dilated thin-walled retinal vessels, but unequivocal retinal NV could not be identified and staining for PCNA was negative. These findings indicate that sustained intravitreal release of VEGF causes widespread retinal vascular dilation and breakdown of the BRB. Retinal NV seems to require persistent high levels of VEGF at the retinal surface and can be achieved in rabbits providing a potentially useful model of retinal NV, but is difficult to achieve in primates. The extensive VEGF-induced disruption of the blood-retinal barrier suggests that VEGF antagonists may provide a new therapy for patients with ischemic retinopathies and macular edema. (C) 1997 Academic Press Limited.