Zhang Sarah X, Wang Joshua J, Gao Guoquan, Parke Kyoungmin, Ma Jian-xing
Department of Medicine, Department of Cell Biology, University of Oklahoma Health Sciences Center, 941 Stanton L. Young Blvd., Oklahoma City, OK, USA.
J Mol Endocrinol. 2006 Aug;37(1):1-12. doi: 10.1677/jme.1.02008.
It has been shown that the balance between vascular endothelial growth factor (VEGF), a major angiogenic stimulator, and pigment epithelium-derived factor (PEDF), a potent angiogenic inhibitor, is critical for the regulation of vascular permeability and angiogenesis. However, the regulation of the balance is largely unclear. The present study demonstrated that there is a reciprocal interaction between VEGF and PEDF in the retina. PEDF significantly decreased VEGF expression in both retinal capillary endothelial cells (RCEC) and Müller cells. This PEDF effect was confirmed in the retina of rats with oxygen-induced retinopathy. Silencing of the PEDF gene by siRNA in Müller cells resulted in a significant upregulation of VEGF expression at both the RNA and protein levels, suggesting that PEDF is an endogenous negative regulator of VEGF. The further study of the mechanism showed that PEDF inhibited hypoxia-induced increases in VEGF promoter activity, HIF-1 nuclear translocation and mitogen activated protein kinase phosphorylation. These results suggest that PEDF inhibits VEGF expression at the transcriptional level. In addition, PEDF effectively inhibited VEGF binding to RCEC. Moreover, in vitro receptor-binding assay demonstrated that PEDF competed with VEGF for binding to VEGF receptor 2, which may represent a new mechanism for PEDF activity. On the other hand, VEGF significantly downregulated PEDF expression in RCEC, but not in retinal Müller cells, suggesting a VEGF receptor-mediated process. These results suggest that the reciprocal regulation between VEGF and PEDF may play a role in angiogenic control. The decrease in PEDF levels in the retina is at least partially responsible for the increase in VEGF expression and subsequent vascular leakage and neovascularization in diabetes.
研究表明，主要血管生成刺激因子血管内皮生长因子（VEGF）与强效血管生成抑制剂色素上皮衍生因子（PEDF）之间的平衡对于调节血管通透性和血管生成至关重要。然而，这种平衡的调节机制在很大程度上尚不清楚。本研究表明，视网膜中VEGF和PEDF之间存在相互作用。PEDF显著降低视网膜毛细血管内皮细胞（RCEC）和穆勒细胞中VEGF的表达。在氧诱导视网膜病变大鼠的视网膜中证实了这种PEDF效应。通过小干扰RNA（siRNA）沉默穆勒细胞中的PEDF基因导致RNA和蛋白质水平上VEGF表达显著上调，表明PEDF是VEGF的内源性负调节因子。对该机制的进一步研究表明，PEDF抑制缺氧诱导的VEGF启动子活性增加、低氧诱导因子-1（HIF-1）核转位以及丝裂原活化蛋白激酶磷酸化。这些结果表明，PEDF在转录水平上抑制VEGF表达。此外，PEDF有效抑制VEGF与RCEC的结合。而且，体外受体结合试验表明，PEDF与VEGF竞争结合VEGF受体2，这可能代表了PEDF活性的一种新机制。另一方面，VEGF显著下调RCEC中PEDF的表达，但在视网膜穆勒细胞中未下调，提示这是一个VEGF受体介导的过程。这些结果表明，VEGF和PEDF之间的相互调节可能在血管生成控制中起作用。视网膜中PEDF水平的降低至少部分导致了糖尿病中VEGF表达增加以及随后的血管渗漏和新生血管形成。
