Shen W-Y, Lai C M, Graham C E, Binz N, Lai Y K Y, Eade J, Guidolin D, Ribatti D, Dunlop S A, Rakoczy P E
Centre of Ophthalmology and Visual Science, The University of Western Australia, Nedlands, Perth, WA, Australia.
Diabetologia. 2006 Jul;49(7):1690-701. doi: 10.1007/s00125-006-0274-8. Epub 2006 May 10.
AIMS/HYPOTHESIS: Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of diabetic retinopathy. We investigated whether transgenic mice with moderate VEGF expression in photoreceptors (trVEGF029) developed changes similar to diabetic retinopathy and whether retinopathy progressed with time.
Human VEGF(165) (hVEGF(165)) expression was analysed using ELISA and quantitative RT-PCR; serum glucose levels were also measured. Fundus fluorescein angiography (FA) was used to screen the degree of retinopathy from 6 weeks. Dynamic changes in the density of retinal microvasculature, as well as other changes similar to diabetic retinopathy, including retinal leucostasis, capillary endothelial cell and pericyte loss, and numbers of acellular capillaries, were quantified.
trVEGF029 mice were normoglycaemic and showed a moderate, short-term hVEGF(165) upregulation for up to 3 weeks. Changes in the retinal microvasculature not only mimicked those seen in diabetic retinopathy, but also showed similar pathological progression with time. FA at 6 weeks identified two phenotypes, mild and moderate, which were distinguished by the extent of vascular leakage. Quantitative analysis of diabetic retinopathy-like changes revealed that these parameters were tightly correlated with the initial degree of vascular leakage; low levels reflected slow and limited retinal microvascular changes in mild cases and high levels reflected more rapid and extensive changes in moderate cases.
CONCLUSIONS/INTERPRETATION: The data suggest that even an early short-term elevation in hVEGF(165) expression might set a train of events that lead to progressive retinopathy. Induction of many features characteristic of diabetic retinopathy in trVEGF029 enables mechanisms leading to the disease state to be examined, and provides a relevant animal model for testing novel therapeutics.
目的/假设：血管内皮生长因子（VEGF）在糖尿病视网膜病变的发病机制中起关键作用。我们研究了光感受器中VEGF表达适度的转基因小鼠（trVEGF029）是否会出现与糖尿病视网膜病变相似的变化，以及视网膜病变是否会随时间进展。
使用酶联免疫吸附测定（ELISA）和定量逆转录聚合酶链反应（RT-PCR）分析人VEGF(165)（hVEGF(165)）的表达；同时测量血糖水平。从6周龄开始，使用眼底荧光血管造影（FA）筛查视网膜病变程度。对视网膜微血管密度的动态变化以及其他与糖尿病视网膜病变相似的变化进行定量分析，这些变化包括视网膜白细胞停滞、毛细血管内皮细胞和周细胞丢失以及无细胞毛细血管数量。
trVEGF029小鼠血糖正常，在长达3周的时间内hVEGF(165)呈适度、短期上调。视网膜微血管的变化不仅与糖尿病视网膜病变中的变化相似，而且随时间呈现出相似的病理进展。6周龄时的FA确定了两种表型，轻度和中度，它们通过血管渗漏程度来区分。对糖尿病视网膜病变样变化的定量分析表明，这些参数与血管渗漏的初始程度密切相关；低水平反映轻度病例中视网膜微血管变化缓慢且有限，高水平反映中度病例中变化更快且更广泛。
结论/解读：数据表明，即使hVEGF(165)表达早期短期升高也可能引发一系列导致进行性视网膜病变的事件。trVEGF029小鼠诱导出许多糖尿病视网膜病变的特征，这有助于研究导致疾病状态的机制，并为测试新型治疗方法提供了相关动物模型。
