Effect of VEGF-A on expression of profibrotic growth factor and extracellular matrix genes in the retina
Effect of VEGF-A on expression of profibrotic growth factor and extracellular matrix genes in the retina
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DOI：
10.1167/iovs.06-0804
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发表时间：
2007-09-01
影响因子：
4.4
通讯作者：
Klaassen, Ingeborg
中科院分区：
文献类型：
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作者：
Kuiper, Esther J.;Hughes, John M.;Klaassen, Ingeborg
目的.血管内皮生长因子-A（VEGF）导致临床前糖尿病视网膜病变（PCDR）中血管通透性增加和白细胞粘附。PCDR的另一个标志是毛细血管基底膜（BM）增厚。最近，已显示VEGF在培养的内皮细胞中诱导促纤维化基因如转化生长因子（TGF）-β 1和结缔组织生长因子（CTGF或CCN 2）的表达。此外，VEGF的中和防止了体内糖尿病小鼠的BM增厚。作者推测VEGF通过诱导促纤维化生长因子和细胞外基质（ECM）成分的表达直接导致糖尿病视网膜BM增厚。通过实时定量PCR、Western印迹分析和免疫组织化学方法评价玻璃体内注射VEGF后大鼠视网膜ECM相关基因的转录和蛋白水平。此外，在牛视网膜血管细胞在体外的VEGF刺激的反应相同的基因的表达谱进行了研究。玻璃体内注射VEGF诱导CYR 61（CCN 1）、CTGF、TGF-β 1、金属蛋白酶组织抑制剂（TIMP）-1和纤连蛋白的视网膜转录，以及CYR 61、CTGF、TGF-β 1和纤连蛋白的蛋白表达。在体外VEGF刺激的牛视网膜内皮细胞和周细胞中，基因表达谱与体内完整视网膜中的基因表达谱相似。VEGF在体内视网膜中以及在体外培养的视网膜血管细胞中诱导促纤维化生长因子和细胞外基质基因。目前的研究结果与了解临床前DR的发病机制有关，其中VEGF的早期上调可能通过诱导ECM相关基因引起BM增厚。
PURPOSE. Vascular endothelial growth factor-A ( VEGF) causes increased vascular permeability and leukocyte adhesion in preclinical diabetic retinopathy ( PCDR). Another hallmark of PCDR is thickening of the capillary basement membrane ( BM). Recently, VEGF has been shown to induce expression of pro-fibrotic genes such as transforming growth factor ( TGF)-beta 1 and connective tissue growth factor ( CTGF or CCN2) in cultured endothelial cells. Moreover, neutralization of VEGF prevented BM thickening in diabetic mice in vivo. The authors hypothesize that VEGF directly contributes to BM thickening in the diabetic retina by inducing expression of profibrotic growth factors and extracellular matrix (ECM) components.METHODS. Transcription and protein levels of ECM-related genes were evaluated in the rat retina after intravitreal VEGF injection by real-time quantitative PCR, Western blot analysis, and immunohistochemistry. In addition, expression profiles of the same genes in response to VEGF stimulation were investigated in bovine retinal vascular cells in vitro.RESULTS. Intravitreal VEGF injection induced retinal transcription of CYR61 (CCN1), CTGF, TGF-beta 1, tissue inhibitor of metalloproteases ( TIMP)-1 and fibronectin, and protein expression of CYR61, CTGF, TGF-beta 1 and fibronectin. In bovine retinal endothelial cells and pericytes stimulated by VEGF in vitro, gene expression profiles were similar to those in the intact retina in vivo.CONCLUSIONS. VEGF induces profibrotic growth factors and extracellular matrix genes in the retina in vivo, as well as in cultured retinal vascular cells in vitro. The current findings have relevance for understanding the pathogenesis of preclinical DR, where early upregulation of VEGF may cause BM thickening by induction of ECM-related genes.