Lu Kangmo, Zhou Yuehua, Kaufman Ken, Mott Robert, Ma Jian-xing
Department of Medicine Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
J Mol Endocrinol. 2007 Apr;38(4):423-32. doi: 10.1677/JME-06-0015.
Vascular endothelial growth factor (VEGF) is a potent inflammation, vascular permeability, and angiogenic factor. Variations of the VEGF gene are implicated in the pathogenesis of diabetic retinopathy. Previous studies have shown that Brown Norway (BN) rats have higher retinal VEGF levels and more severe retinal vascular leakage than Sprague-Dawley (SD) rats in response to ischemia and diabetes. To investigate the molecular mechanism of vascular leakage in this animal model, F2 progeny were generated by crossbreeding BN and SD rats. Neonatal rats were exposed to hyperoxia to induce oxygen-induced retinopathy (OIR) models. The F2 rats in response to ischemia have shown a linear distribution of retinal VEGF levels, which is significantly and positively correlated to retinal vascular leakage. We identified a single nucleotide polymorphism (SNP) at upstream stimulating factor-binding site in the VEGF promoter region between BN and SD rats. No differences were found in retinal vascular permeability or VEGF levels between F2 rats with BN, SD, and BN/SD alleles of VEGF SNP. The increased retinal VEGF levels are correlated to ischemia-induced retinal vascular leakage in the OIR rat model. The VEGF mRNA and promoter are not responsible for increased retinal VEGF level and vascular permeability. The up-regulation of VEGF expression activated by a yet to be identified upstream factor or mediator affecting VEGF stability may be associated with a high susceptibility to retinal vascular leakage in BN rats.
血管内皮生长因子（VEGF）是一种强效的炎症、血管通透性和血管生成因子。VEGF基因的变异与糖尿病视网膜病变的发病机制有关。先前的研究表明，与Sprague-Dawley（SD）大鼠相比，棕色挪威（BN）大鼠在缺血和糖尿病状态下视网膜VEGF水平更高，视网膜血管渗漏更严重。为了研究该动物模型中血管渗漏的分子机制，通过将BN大鼠和SD大鼠杂交产生了F2代后代。新生大鼠暴露于高氧环境以诱导氧诱导性视网膜病变（OIR）模型。对缺血作出反应的F2大鼠显示出视网膜VEGF水平呈线性分布，这与视网膜血管渗漏显著正相关。我们在BN大鼠和SD大鼠的VEGF启动子区域的上游刺激因子结合位点鉴定出一个单核苷酸多态性（SNP）。具有VEGF SNP的BN、SD和BN/SD等位基因的F2大鼠在视网膜血管通透性或VEGF水平上未发现差异。在OIR大鼠模型中，视网膜VEGF水平升高与缺血诱导的视网膜血管渗漏相关。VEGF mRNA和启动子与视网膜VEGF水平升高和血管通透性增加无关。由尚未确定的影响VEGF稳定性的上游因子或介质激活的VEGF表达上调可能与BN大鼠对视网膜血管渗漏的高易感性有关。
