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Vascular endothelial growth factor increases heme oxygenase‐1 protein expression in the chick embryo chorioallantoic membrane
Author(s) -
Fernandez Mercedes,
Bonkovsky Herbert L
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705272
Subject(s) - chorioallantoic membrane , angiogenesis , heme oxygenase , vascular endothelial growth factor , vascular endothelial growth factor a , heme , biology , protein kinase a , microbiology and biotechnology , chemistry , biochemistry , kinase , cancer research , enzyme , vegf receptors
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. 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. Treatment of CAMs with VEGF for 48 h caused a significant increase in HO‐1 protein expression, simultaneously with angiogenesis. 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. 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. In addition, the protein kinase C inhibitor staurosporine significantly attenuated, in a dose‐dependent manner, the VEGF‐stimulated HO‐1 induction observed in CAMs. 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.British Journal of Pharmacology (2003) 139 , 634–640. doi: 10.1038/sj.bjp.0705272