Reciprocal regulation between nitric oxide and vascular endothelial growth factor in angiogenesis.
Reciprocal regulation between nitric oxide and vascular endothelial growth factor in angiogenesis.
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DOI：
10.18388/abp.2003_3713
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发表时间：
2003
影响因子：
1.7
通讯作者：
H. Kimura;H. Esumi
中科院分区：
文献类型：
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作者：
H. Kimura;H. Esumi
在生理上，血管生成受到严格的调控，否则它会导致病理过程，如肿瘤、炎症性疾病、妇科疾病和糖尿病视网膜病变。血管内皮生长因子(VEGF)是一种强有力的血管生成的关键诱导剂。血管内皮生长因子基因的表达受多种刺激的调节。低氧是诱导血管内皮细胞生长因子表达的最强诱因之一。低氧诱导因子-1(HIF-1)是低氧介导的血管内皮生长因子基因上调的关键转录因子。据报道，一氧化氮(NO)和低氧通过增强HIF-1的活性上调血管内皮生长因子基因。Akt/蛋白激酶B(PKB)通路可能参与了NO介导的HIF-1在有限细胞系中的激活。有报道称NO对HIF-1和血管内皮生长因子活性有负性影响。这些相互矛盾的NO影响数据可能主要归因于NO的释放量。事实上，在相同的条件下，只需改变一氧化氮的量，就可以成为血管内皮生长因子基因的正或负调节因子。血管内皮生长因子介导的血管生成需要激活的内皮型一氧化氮合酶(ENOS)产生NO。血管内皮生长因子激活eNOS涉及Akt/PKB、Ca(2+)/钙调蛋白和蛋白激酶C等多种途径，NO介导的血管内皮生长因子的表达受HIF-1和HO-1活性的调节，而血管内皮生长因子介导的eNOS产生的NO也受HIF-1和HO-1活性的调节，这取决于产生的NO的数量。NO和血管内皮生长因子之间的这种相互作用关系可能有助于调节正常组织的血管生成。
Physiologically, angiogenesis is tightly regulated, or otherwise it leads to pathological processes, such as tumors, inflammatory diseases, gynecological diseases and diabetic retinopathy. The vascular endothelial growth factor (VEGF) is a potent and critical inducer of angiogenesis. The VEGF gene expression is regulated by a variety of stimuli. Hypoxia is one of the most potent inducers of the VEGF expression. The hypoxia inducible factor 1 (HIF-1) plays as a key transcription factor in hypoxia-mediated VEGF gene upregulation. Nitric oxide (NO) as well as hypoxia is reported to upregulate the VEGF gene by enhancing HIF-1 activity. The Akt/protein kinase B (PKB) pathway may be involved in NO-mediated HIF-1 activation in limited cell lines. There are some reports of negative effects of NO on HIF-1 and VEGF activity. These conflicting data of NO effects may be attributed mainly to the amount of released NO. Indeed, NO can be a positive or negative modulator of the VEGF gene under the same conditions simply by changing its amounts. The VEGF-mediated angiogenesis requires NO production from activated endothelial NO synthase (eNOS). Activation of eNOS by VEGF involves several pathways including Akt/PKB, Ca(2+)/calmodulin, and protein kinase C. The NO-mediated VEGF expression can be regulated by HIF-1 and heme oxygenase 1 (HO-1) activity, and the VEGF-mediated NO production by eNOS can be also modulated by HIF-1 and HO-1 activity, depending upon the amount of produced NO. These reciprocal relations between NO and VEGF may contribute to regulated angiogenesis in normal tissues.