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：
10.1097/00006982-199805000-00032
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发表时间：
1998-05
影响因子：
3.4
通讯作者：
H. Ozaki;H. Hayashi;S. Vinores;Y. Moromizato;P. Campochiaro;K. Oshima
中科院分区：
文献类型：
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作者：
H. Ozaki;H. Hayashi;S. Vinores;Y. Moromizato;P. Campochiaro;K. Oshima
血管内皮生长因子（VEGF）已被确定为视网膜新生血管形成（NV）的可能介质，但尚不确定单独的VEGF是否足以引起视网膜NV。我们试图通过植入乙烯-醋酸乙烯共聚物小球，缓慢释放VEGF到兔和灵长类动物的玻璃体腔来研究这个问题。通过间接检眼镜检查、眼底照相和荧光素血管造影检查眼睛，然后在不同时间点处死动物，进行免疫细胞化学和超微结构评价。将含有30微克人重组VEGF的小球植入兔的玻璃体腔后7天，视网膜血管扩张并弯曲，在第14天至第21天之间，在所有眼睛中观察到视网膜NV。血管造影显示异常血管大量染料渗漏。增殖细胞核抗原（PCNA）免疫组化染色显示视网膜表面新生血管内皮细胞核呈阳性染色。植入含有载体的对照颗粒的六只眼睛和植入含有30微克单独人血清白蛋白的颗粒的两只眼睛未显示视网膜血管异常。将含有100微克VEGF的颗粒植入灵长类动物的玻璃体腔中导致虹膜NV和视网膜血管扩张和迂曲，非常类似于在患有缺血性视网膜病的人类中所见。血清白蛋白的免疫组化染色显示血视网膜屏障（BRB）的广泛严重破坏。组织学检查显示视网膜薄壁血管扩张，但无法确定明确的视网膜NV，PCNA染色呈阴性。这些发现表明VEGF的持续玻璃体内释放引起广泛的视网膜血管扩张和BRB的破坏。视网膜NV似乎需要在视网膜表面持续高水平的VEGF，并且可以在兔中实现，从而提供视网膜NV的潜在有用的模型，但在灵长类动物中难以实现。VEGF诱导的血-视网膜屏障的广泛破坏表明VEGF拮抗剂可能为缺血性视网膜病和黄斑水肿患者提供新的治疗方法。
Vascular endothelial growth factor (VEGF) has been identified as a possible mediator of retinal neovascularisation (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 micrograms of human recombinant VEGF 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 micrograms of human serum albumin alone showed no retinal vascular abnormalities. Implantation of pellets containing 100 micrograms 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.