Regulation of vascular endothelial growth factor expression by insulin-like growth factor I
Regulation of vascular endothelial growth factor expression by insulin-like growth factor I
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DOI：
10.2337/diabetes.46.10.1619
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发表时间：
1997-10-01
期刊：
影响因子：
7.7
通讯作者：
Adamis, AP
中科院分区：
文献类型：
--
作者：
Punglia, RS;Lu, M;Adamis, AP
胰岛素样生长因子-I和血管内皮生长因子水平与人视网膜缺血相关的眼内新生血管有关。由于在视网膜缺血的动物模型中，血管内皮生长因子是虹膜和视网膜新生血管所必需的，我们测试了胰岛素样生长因子-I是否可以通过增加血管内皮生长因子基因的表达作为间接血管生成因子，胰岛素样生长因子-I以浓度依赖的方式增加视网膜色素上皮细胞血管内皮生长因子的表达，其EC50为7nmol/L(53.6 ng/ml)。50nmol/L(383 ng/mlIGF-I)作用于RPE细胞和牛血管内皮细胞后，血管内皮细胞中VEGFmRNA的表达在2 h内达到高峰，经IGF-I处理的RPE细胞条件培养液中的VEGF蛋白水平升高，并刺激毛细血管内皮细胞增殖，用中和抗体阻断IGF-I受体可抑制RPE细胞中VEGF的表达，缺氧和IGF-I诱导的RPE细胞中VEGFmRNA和蛋白水平的升高是相加的，且这种升高不依赖于内源性IGF-I。在RPE细胞中，IGF-I增强了血管内皮生长因子启动子的活性，但对血管内皮生长因子转录半衰期没有影响。综上所述，在5-100nmol/L浓度范围内，加入IGF-I可增加RPE细胞中VEGFm RNA和分泌蛋白的水平，在RPE细胞中，VEGF表达的增加主要是通过增强其转录和IGF-I受体来实现的，而IGF-I水平的升高可能通过促进视网膜血管内皮生长因子基因的表达而促进新生血管的形成。
Insulin-like growth factor I (IGF-I) and vascular endothelial growth factor (VEGF) levels are correlated with retinal ischemia-associated intraocular neovascularization in humans, Since VEGF is required for iris and retinal neovascularization in animal models of retinal ischemia, we tested whether IGF-I could act as an indirect angiogenic factor by increasing VEGF gene expression, IGF-I increased retinal pigment epithelial (RPE) cell VEGF mRNA in a concentration-dependent manner with an EC50 of 7 nmol/l (53.6 ng/ml), RPE and bovine smooth muscle cells exposed to 50 nmol/l (383 ng/ml) IGF-I achieved peak VEGF mRNA expression within 2 h. IGF-I-treated RPE cells increased VEGF protein levels in conditioned media and stimulated capillary endothelial cell proliferation, Blockade of the IGF-I receptor with a neutralizing antibody abrogated the VEGF increases in RPE cells, Further, hypoxia-mediated and IGF-I-mediated increases in VEGF mRNA and protein levels were additive in RPE cells, and the hypoxia-induced VEGF increases were independent of endogenous IGF-I. VEGF promoter activity was enhanced by IGF-I in RPE cells, but VEGF transcript half-life was unaltered, In summary, the supplementation of RPE and smooth muscle cell cultures with IGF-I at 5-100 nmol/l increased VEGF mRNA and secreted protein levels, The VEGF increases in RPE cells occurred primarily through enhanced transcription of the VEGF gene and via the IGF-I receptor, Elevated IGF-I levels may promote neovascularization through increased retinal VEGF gene expression.