Vascular endothelial growth factor increases heme oxygenase-1 protein expression in the chick embryo chorioallantoic membrane
Vascular endothelial growth factor increases heme oxygenase-1 protein expression in the chick embryo chorioallantoic membrane
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DOI：
10.1038/sj.bjp.0705272
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发表时间：
2003-06-01
影响因子：
7.3
通讯作者：
Bonkovsky, HL
中科院分区：
文献类型：
--
作者：
Fernandez, M;Bonkovsky, HL
1血管内皮生长因子（VEGF）是一种强有力的血管生成因子。最近有人提出，诱导型血红素加氧酶（HO-1）亚型可能在血管生成中发挥作用。2本研究的目的是确定，在鸡胚绒毛尿囊膜（CAM）中，VEGF是否增加HO-1蛋白表达，如果是，通过何种分子机制，以及HO-1活性是否是VEGF诱导的血管生成所必需的。3用VEGF处理CAM 48小时引起HO-1蛋白表达的显著增加，4 VEGF刺激的CAM中的血管生成被HO抑制剂锌中卟啉（ZnMP）显著减弱。用铜中卟啉（CuMP）没有观察到ZnMP的这种抑制作用，铜中卟啉是一种金属卟啉，具有与ZnMP相似的结构，但不抑制HO酶活性。5细胞内钙螯合剂1，2-双（2-氨基苯氧基）乙烷-N，N，N '，N'-四乙酸-乙酰氧基甲酯（BAPTA-AM）显著减弱了CAM中VEGF引起的HO-1蛋白的过表达。BAPTA-AM的作用反过来又被钙离子载体A-23187补偿。6此外，蛋白激酶C抑制剂星形孢菌素以剂量依赖性方式显著减弱了在CAM中观察到的VEGF刺激的HO-1诱导。7这些结果首次证明，VEGF通过依赖于胞浆钙水平增加和蛋白激酶C活化的机制上调CAM中体内HO-1蛋白表达。我们的研究结果还表明，HO-1的活性是必要的VEGF诱导血管生成CAM。
1 Vascular endothelial growth factor ( VEGF) is a potent angiogenic factor. It has been recently suggested that the inducible heme oxygenase (HO-1) isoform may play a role in angiogenesis.2 The aims of this study were to determine, in chicken embryo chorioallantoic membranes ( CAM), whether VEGF increases HO-1 protein expression, and, if so, by which molecular mechanism, and whether HO-1 activity is required for VEGF-induced angiogenesis.3 Treatment of CAMs with VEGF for 48 h caused a significant increase in HO-1 protein expression, simultaneously with angiogenesis.4 VEGF-stimulated angiogenesis in CAMs was markedly attenuated by the HO inhibitor zinc mesoporphyrin ( ZnMP). This inhibitory effect of ZnMP was not observed with copper mesoporphyrin (CuMP), a metalloporphyrin that has a similar structure to ZnMP but does not inhibit HO enzymatic activity.5 Overexpression of HO-1 protein elicited by VEGF in CAMs was significantly attenuated by the intracellular calcium chelator 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM). The effects of BAPTA-AM were, in turn, compensated by the calcium ionophore A-23187.6 In addition, the protein kinase C inhibitor staurosporine significantly attenuated, in a dose-dependent manner, the VEGF-stimulated HO-1 induction observed in CAMs.7 These results demonstrate, for the first time, that VEGF upregulates HO-1 protein expression in vivo in CAMs by a mechanism dependent on an increase in cytosolic calcium levels and activation of protein kinase C. Our findings also suggest that HO-1 activity is necessary for VEGF-induced angiogenesis in CAMs.