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J. Biol. Chem., Vol. 278, Issue 21, 19518-19525, May 23, 2003

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Regulation of Vascular Endothelial Growth Factor Binding and Activity by Extracellular pH^*

Adrienne L. Goerges and Matthew A. Nugent 

From the Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118

Angiogenesis, the growth of new blood vessels, is regulated by a number of factors, including hypoxia and vascular endothelial growth factor (VEGF). Although the effects of hypoxia have been 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, because VEGF₁₆₅ and VEGF₁₂₁ showed increased retention on heparin-Sepharose at pH 5.5 compared with 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 signal-regulated kinases 1 and 2 (Erk1/2). VEGF₁₆₅ and VEGF₁₂₁ activation of Erk1/2 at pH 7.5 peaked after 5 min, whereas 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.

Received for publication, November 3, 2002 , and in revised form, March 11, 2003.

To whom correspondence should be addressed: Dept. of Biochemistry, Boston University School of Medicine, Boston, MA 02118. Tel.: 617-638-4169; Fax: 617-638-5339; E-mail: nugent{at}biochem.bumc.bu.edu.

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