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Papers In Press, published online ahead of print March 11, 2003
Biochemistry, Boston University School of Medicine, Boston, MA 02118
Corresponding Author: nugent{at}biochem.bumc.bu.edu
Angiogenesis, the growth of new blood vessels, is regulated by a number of factors including hypoxia and vascular endothelial growth factor (VEGF). While the effects of hypoxia have been the studied intensely, less attention has been given to other extracellular parameters such as pH. Thus, the present study investigates the consequences of acidic pH on VEGF binding and activity in endothelial cell cultures. We found that the binding of VEGF165 and VEGF121 to endothelial cells increased as the extracellular pH was decreased from 7.5 to 5.5. Binding of VEGF165 and VEGF121 to endothelial extracellular matrix was also increased at acidic pH. These effects were, in part, a reflection of increased heparin binding as VEGF165 and VEGF121 showed increased retention on heparin-Sepharose at pH 5.5 compared to pH 7.5. Consistent with these findings, soluble heparin competed for VEGF binding to endothelial cells under acidic conditions. However, at neutral pH (7.5) low concentrations of heparin (0.1-1.0 µg/ml) potentiated VEGF binding. Extracellular pH also regulated VEGF activation of the extracellular regulated kinases 1 and 2 (Erk1/2). VEGF165 and VEGF121 activation of Erk1/2 at pH 7.5 peaked after 5 min, while at pH 6.5 the peak was shifted to 10 min. At pH 5.5, neither VEGF isoform was able to activate Erk1/2, suggesting that the increased VEGF bound to the cells at low pH was sequestered in a stored state. Therefore, extracellular pH might play an important role in regulating VEGF interactions with cells and the extracellular matrix, which can modulate VEGF activity.
J. Biol. Chem, 10.1074/jbc.M211208200
Submitted on November 3, 2002
Revised on March 11, 2003
Accepted on March 11, 2003
Regulation of vascular endothelial growth factor binding and activity by extracellular pH
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